Methods for treating asthmatic conditions

ABSTRACT

This invention provides methods for treating in mammals asthma and asthmatic conditions using substituted indole compounds of the general formula: 
                         
and pharmaceutically acceptable salt forms thereof, and methods for using the compounds as inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A 2  enzymes, and for the medical treatment, prevention and inhibition of pain and inflammation.

The present invention relates tomethods of treating or alleviatingasthma and the symptoms of asthma utilizing chemical inhibitors of theactivity of various phospholipase enzymes, particularly cytosolicphospholipase A₂ enzymes (cPLA₂), more particularly including inhibitorsof cytosolic phospholipase A₂ alpha enzymes (cPLA_(2α)).

BACKGROUND OF THE INVENTION

Leukotrienes and prostaglandins are important mediators of inflammation,each of which contributes to the development of an inflammatory responsein a different way. Leukotrienes recruit inflammatory cells such asneutrophils to an inflamed site, promote the extravasation of thesecells and stimulate release of superoxide and proteases which damage thetissue. Leukotrienes also play a pathophysiological role in thehypersensitivity experienced by asthmatics [See, e.g. B. Samuelson etal., Science, 237:1171-76 (1987)]. Prostaglandins enhance inflammationby increasing blood flow and therefore infiltration of leukocytes toinflamed sites. Prostaglandins also potentiate the pain response inducedby stimuli.

Prostaglandins and leukotrienes are unstable and are not stored incells, but are instead synthesized [W. L. Smith, Biochem. J.,259:315-324 (1989)] from arachidonic acid in response to stimuli.Prostaglandins are produced from arachidonic acid by the action of COX-1and COX-2 enzymes. Arachidonic acid is also the substrate for thedistinct enzyme pathway leading to the production of leukotrienes.

Arachidonic acid which is fed into these two distinct inflammatorypathways is released from the sn-2 position of membrane phospholipids byphospholipase A₂ enzymes (hereinafter PLA₂). The reaction catalyzed byPLA₂ is believed to represent the rate-limiting step in the process oflipid mediated biosynthesis and the production of inflammatoryprostaglandins and leukotrienes. When the phospholipid substrate of PLA₂is of the phosphotidyl choline class with an ether linkage in the sn-1position, the lysophospholipid produced is the immediate precursor ofplatelet activating factor (hereafter called PAF), another potentmediator of inflammation [S. I. Wasserman, Hospital Practice, 15:49-58(1988)].

Most anti-inflammatory therapies have focused on preventing productionof either prostglandins or leukotrienes from these distinct pathways,but not on all of them. For example, ibuprofen, aspirin, andindomethacin are all NSAIDs which inhibit the production ofprostaglandins by COX-1/COX-2 inhibition, but have no effect on theinflammatory production of leukotrienes from arachidonic acid in theother pathways. Conversely, zileuton inhibits only the pathway ofconversion of arachidonic acid to leukotrienes, without affecting theproduction of prostaglandins. None of these widely-usedanti-inflammatory agents affects the production of PAF.

Consequently the direct inhibition of the activity of PLA₂ has beensuggested as a useful mechanism for a therapeutic agent, i.e., tointerfere with the inflammatory response. [See, e.g., J. Chang et al,Biochem. Pharmacol., 36:2429-2436 (1987)].

A family of PLA₂ enzymes characterized by the presence of a secretionsignal sequenced and ultimately secreted from the cell have beensequenced and structurally defined. These secreted PLA₂s have anapproximately 14 kD molecular weight and contain seven disulfide bondswhich are necessary for activity. These PLA₂s are found in largequantities in mammalian pancreas, bee venom, and various snake venom.[See, e.g., references 13-15 in Chang et al, cited above; and E. A.Dennis, Drug Devel. Res., 10:205-220 (1987).] However, the pancreaticenzyme is believed to serve a digestive function and, as such, shouldnot be important in the production of the inflammatory mediators whoseproduction must be tightly regulated.

The primary structure of the first human non-pancreatic PLA₂ has beendetermined. This non-pancreatic PLA₂ is found in platelets, synovialfluid, and spleen and is also a secreted enzyme. This enzyme is a memberof the aforementioned family. [See, J. J. Seilhamer et al, J. Biol.Chem., 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem.,264:5768-5775 (1989); and A. Kando et al, Biochem. Biophys. Res. Comm.,163:42-48 (1989)]. However, it is doubtful that this enzyme is importantin the synthesis of prostaglandins, leukotrienes and PAF, since thenon-pancreatic PLA₂ is an extracellular protein which would be difficultto regulate, and the next enzymes in the biosynthetic pathways for thesecompounds are intracellular proteins. Moreover, there is evidence thatPLA₂ is regulated by protein kinase C and G proteins [R. Burch and J.Axelrod, Proc. Natl. Acad. Sci. U.S.A., 84:6374-6378 (1989)] which arecytosolic proteins which must act on intracellular proteins. It would beimpossible for the non-pancreatic PLA₂ to function in the cytosol, sincethe high reduction potential would reduce the disulfide bonds andinactivate the enzyme.

A murine PLA₂ has been identified in the murine macrophage cell line,designated RAW 264.7. A specific activity of 2 mols/min/mg, resistant toreducing conditions, was reported to be associated with theapproximately 60 kD molecule. However, this protein was not purified tohomogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta.,963:476-492 (1988)]. The references cited above are incorporated byreference herein for information pertaining to the function of thephospholipase enzymes, particularly PLA₂.

A cytosolic phospholipase A₂ alpha (hereinafter “cPLA₂α”) has also beenidentified and cloned. See, U.S. Pat. Nos. 5,322,776 and 5,354,677,which are incorporated herein by reference as if fully set forth. Theenzyme of these patents is an intracellular PLA₂ enzyme, purified fromits natural source or otherwise produced in purified form, whichfunctions intracellularly to produce arachidonic acid in response toinflammatory stimuli.

Now that several phospholipase enzymes have been identified, it would bedesirable to identify chemical inhibitors of the action of specificphospholipase enzymes, which inhibitors could be used to treatinflammatory conditions, particularly where inhibition of production ofprostaglandins, leukotrienes and PAF are all desired results. Thereremains a need in the art for an identification of suchanti-inflammatory agents for therapeutic use in a variety of diseasestates.

DETAILED DESCRIPTION OF THE INVENTION

This invention comprises a method of treatment, inhibition, alleviationor relief of asthma and asthmatic conditions in a mammal, preferably ina human, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a compound of the formula:

wherein:

R is selected from the formulae —(CH₂)_(n)-A, —(CH₂)_(n)—S-A, or—(CH₂)_(n)—O-A, wherein A is selected from the moieties:

wherein

D is C₁-C₆ lower alkyl, C₁-C₆ lower alkoxy, C₃-C₆ cycloaklyl —CF₃ or—(CH₂)₁₋₃—CF₃;

B and C are independently selected from phenyl, pyridinyl, pyrimidinyl,furanyl, thiophenyl or pyrrolyl groups, each optionally substituted byfrom 1 to 3, preferably 1 to 2, substituents selected independently fromH, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy,—NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), —NO₂, or by a 5- or6-membered heterocyclic or heteroaromatic ring containing 1 or 2heteroatoms selected from O, N or S; or

-   -   n is an integer from 0 to 3;    -   n₁ is an integer from 1 to 3;    -   n₂ is an integer from 0 to 4;    -   n₃ is an integer from 0 to 3;    -   n₄ is an integer from 0 to 2;

X₁ is selected from a chemical bond, —S—, —O—, —S(O)—, —S(O)₂—, —NH—,—NHC(O)—, —C═C—,

R₁ is a moiety selected from C₁-C₆ alkyl, C₁-C₆ fluorinated alkyl, C₃-C₆cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, CN, —N(C₁-C₆alkyl)₂, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, napthyl,morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl,imidazolyl, piperizinyl, thiazolidinyl, thiomorpholinyl, tetrazole,indole, benzoxazole, benzofuran, imidazolidine-2-thione, 7,7,dimethyl-bicyclo[2.2.1]heptan-2-one, Benzo[1,2,5]oxadiazole,2-Oxa-5-aza-bicyclo[2.2.1]heptane, Piperazin-2-one or pyrrolyl groups,each optionally substituted by from 1 to 3, preferably 1 to 2,substituents independently selected from H, halogen, —CN, —CHO, —CF₃,OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, —SO₂(C₁-C₃ alkyl), —SO₂NH₂, —SO₂NH(C₁-C₃ alkyl),—SO₂N(C₁-C₃ alkyl)₂, —COOH, —CH₂—COOH, —CH₂—N(C₁-C₆ alkyl), —CH₂—N(C₁-C₆alkyl)₂, —CH₂—NH₂, pyridine, 2-Methyl-thiazole, morpholino,1-Chloro-2-methyl-propyl, —C₁-C₆thioalkyl, phenyl (further optionallysubstituted with halogens), benzyloxy, (C₁-C₃ alkyl)C(O)CH₃, (C₁-C₃alkyl)OCH₃, C(O)NH₂, or

X₂ is selected from —O—, —CH₂—, —S—, —SO—, —SO₂—, —NH—, —C(O)—,

R₂ is a ring moiety selected from phenyl, pyridinyl, pyrimidinyl, furyl,thienyl or pyrrolyl groups, the ring moiety being substituted by a groupof the formula —(CH₂)_(n4)—CO₂H or a pharmaceutically acceptable acidmimic or mimetic; and also optionally substituted by 1 or 2 additionalsubstituents independently selected from H, halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂,—N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

R₃ is selected from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂;

R₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, —N—C(O)—N(C₁-C₃ alkyl)₂, —N—C(O)—NH(C₁-C₃ alkyl),—N—C(O)—O—(C₁-C₃ alkyl), —SO₂—C₁-C₆ alkyl, —S—C₃-C₆ cycloalkyl,—S—CH₂—C₃-C₆ cycloalkyl, —SO₂—C₃-C₆ cycloalkyl, , —SO₂—CH₂—C₃-C₆cycloalkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, —O—C₃-C₆cycloalkyl, , —O—CH₂—C₃-C₆ cycloalkyl, phenyl, benzyl, benzyloxy,morpholino or other heterocycles such as pyrrolidino, piperidine,piperizine furan, thiophene, imidazole, tetrazole, pyrazine, pyrazolone,pyrazole, imidazole, oxazole or isoxazole, the rings of each of these R₄groups each being optionally substituted by from 1 to 3 substituentsselected from the group of H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆),—NO₂, —SO₂(C₁-C₃ alkyl), —SO₂NH(C₁-C₃ alkyl), —SO₂N(C₁-C₃ alkyl)₂, orOCF₃;

or a pharmaceutically acceptable salt form thereof.

It will be understood that the C₁-C₆ fluorinated alkyl groups in thedefinition of R₁ may be any alkyl group of 1 to 6 carbon atoms with anyamount of fluorine substitution including, but not limited to, —CF₃,alkyl chains of 1 to 6 carbon atoms terminated by a trifluoromethylgroup, —CF₂CF₃, etc.

Ester forms of the present compounds include the pharmaceuticallyacceptable ester forms known in the art including those which can bemetabolized into the free acid form, such as a free carboxylic acidform, in the animal body, such as the corresponding alkyl esters,cycloalkyl esters, aryl esters and heterocyclic analogues thereof can beused according to the invention, where alkyl esters, cycloalkyl estersand aryl esters are preferred and the alcoholic residue can carryfurther substituents. C₁-C₈ alkyl esters, preferably C₁-C₆ alkyl esters,such as the methyl ester, ethyl ester, propyl ester, isopropyl ester,butyl ester, isobutyl ester, t-butyl ester, pentyl ester, isopentylester, neopentyl ester, hexyl ester, cyclopropyl ester,cyclopropylmethyl ester, cyclobutyl ester, cyclopentyl ester, cyclohexylester, or aryl esters such as the phenyl ester, benzyl ester or tolylester are particularly preferred.

In the definition of X₁, the alkenyl bridging group —C═C— is understoodto indicate either the cis or trans orientation of the indicatedcompound(s).

Pharmaceutically acceptable acid mimics or mimetics useful in thecompounds of this invention include those wherein R₂ is selected fromthe group of:

wherein R_(a) is selected from —CF₃, —CH₃, phenyl, or benzyl, with thephenyl or benzyl groups being optionally substituted by from 1 to 3groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —CF₃,halogen, —OH, or —COOH; R_(b) is selected from —CF₃, —CH₃, —NH₂, phenyl,or benzyl, with the phenyl or benzyl groups being optionally substitutedby from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —CF₃, halogen, —OH, or —COOH; and R_(c) is selected from —CF₃or C₁-C₆ alkyl.

The methods of treatment, inhibition, alleviation or relief of asthmaand asthmatic conditions of this invention include those for ExtrinsicAsthma (also known as Allergic Asthma or Atopic Asthma), IntrinsicAsthma (also known as Nonallergic Asthma or Nonatopic Asthma) orcombinations of both, which has been referred to as Mixed Asthma. Themethods for those experiencing or subject to Extrinsic or AllergicAsthma include incidents caused by or associated with many allergens,such as pollens, spores, grasses or weeds, pet danders, dust, mites,etc. As allergens and other irritants present themselves at varyingpoints over the year, these types of incidents are also referred to asSeasonal Asthma. Also included in the group of Extrinsic Asthmas isbronchial asthmas and allergic bronchopulminary aspergillosis.

Intrinsic Asthmas that may be treated or alleviated by the presentmethods include those caused by infectious agents, such as cold and fluviruses in adults and respiratory syncytial virus (RSV), rhinovirus andinfluenza viruses common in children. Also included are the asthmaconditions which may be brought about in some asthmatics by exerciseand/or cold air. The methods are useful for Intrinsic Asthmas associatedwith industrial and occupational exposures, such as smoke, ozone,noxious gases, sulfur dioxide, nitrous oxide, fumes, includingisocyanates, from paint, plastics, polyurethanes, varnishes, etc., wood,plant or other organic dusts, etc. The methods are also useful forasthmatic incidents associated with food additives, preservatives orpharmacological agents. Common materials of these types are foodcoloring such as Tartrazine, preservatives like bisulfites andmetabisulfites, and pharmacological agents such as aspirin andnon-steroidal anti-inflammatory agents (NSAIDs). Also included aremethods for treating, inhibiting or alleviating the types of asthmareferred to as Silent Asthma or Cough Variant Asthma.

The methods herein are also useful for treatment and alleviation ofIntrinsic Asthma associated with gastroesophageal reflux (GERD), whichcan stimulate bronchoconstriction. GERD, along with retained bodilysecretions, suppressed cough, and exposure to allergens and irritants inthe bedroom can contribute to asthmatic conditions and have beencollectively referred to as Nighttime Asthma or Nocturnal Asthma. Inmethods of treatment, inhibition or alleviation of asthma associatedwith GERD, a pharmaceutically effective amount of the compounds of thisinvention may be used as described herein in combination with apharmaceutically effective amount of an agent for treating GERD. Theseagents include, but are not limited to, proton pump inhibiting agentslike PROTONIX® brand of delayed-release pantoprazole sodium tablets,PRILOSEC® brand omeprazole delayed release capsules, ACIPHEX® brandrebeprazole sodium delayed release tablets or PREVACID® brand delayedrelease lansoprazole capsules. Pharmaceutically effective amounts ofthese agents are understood to include those described in theconventional medical literature, including the pharmaceuticallyeffective doses and regimens for these agents described in the 2001Physicians' Desk Reference (55 Edition), published by Medical EconomicsCompany, Montvale, N.J. 07645-1742.

A first subgroup of compoundsuseful in the methods of this invention, ora pharmaceutically acceptable salt thereof, include those of the groupabove wherein A is the moiety:

and B, C, n, n1, n2, n3, n4, R, X₁, X₂, R₁, R₂, R₃, and R₄ are asdefined above.

A second subgroup of compoundsuseful in the methods of this inventioncomprises those of the first subgroup, above, wherein B and C areunsubstituted phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolylgroups and R, n, n1, n2, n3, n4, R₁, X₁, X₂, R₂, R₃, and R₄ are asdefined above.

A third subgroup of compounds and pharmaceutically acceptable saltformsuseful in the methods of this invention comprise those of thesecond subgroup, above, wherein A is the moiety:

and n, n1, n2, n3, n4, R, X₁, X₂, R₁, R₂, R₃, and R₄ are as definedabove.

A fourth subgroup of compoundsuseful in the methods of this inventioncomprises those of the formulae (II) or (III):

wherein n1, n2, n3, n4, X₁, X₂, R₁, R₂, R₃, and R₄ are as defined above,or a pharmaceutically acceptable salt thereof.

A fifth subgroup of compoundsuseful in the methods of this inventionincludes those of formulae (II) or (III) wherein n3=1, and n1, n2, n4,X₁, X₂, R₁, R₂, R₃, and R₄ are as defined above, or a pharmaceuticallyacceptable salt thereof.

A sixth subgroup of compoundsuseful in the methods of this inventionincludes those of the fifth subgroup, above, wherein R₂ is phenylsubstituted by a group of the formula —(CH₂)_(n4)—CO₂H; and optionallysubstituted by 1 or 2 additional substituents independently selectedfrom H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO; andn1, n2, n4, R₁, X₁, X₂, R₂, R₃, and R₄ are as defined above, or apharmaceutically acceptable salt thereof.

A seventh subgroup of compoundsuseful in the methods of this inventioncomprises those of the formulae (IV) or (V):

wherein:

n₁ is an integer from 1 to 3;

n₂ is an integer from 1 to 3;

R₅, R₆ and R₇ are independently selected from H, halogen, —CN, —CHO,—CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

X₁ is selected from a chemical bond, —S—, —O—, —NH— or —N(C₁-C₃ alkyl)-;

X₂ is selected from —O—, —SO₂— or —CH₂—;

R₂ is a moiety selected from the group of:

R₈ and R₉ are independently selected from H, halogen, —CN, —CHO, —CF₃,—OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂;

n₄ is an integer from 0 to 2;

R₃ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂; and

R₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, morpholino or other heterocycles such aspyrrolidino, piperidine, piperizine, furan, thiophene, imidazole,tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole orisoxazole;

or a pharmaceutically acceptable salt form thereof.

An eighth subgroup of compoundsuseful in the methods of this inventioninclude those of the formulae (VI) or (VII):

wherein:

X₁ is selected from a chemical bond, —S—, —O—, —NH— or —N(C₁-C₃ alkyl)-;

X₂ is selected from —O—, —SO₂—, or —CH₂—;

R₃ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂; and

R₄ is selected from H, halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), —NO₂, morpholino or other heterocycles such aspyrrolidino, piperidine, piperizine, furan, thiophene, imidazole,tetrazole, pyrazine, pyrazolone, pyrazole, imidazole, oxazole orisoxazole;

n₁ is an integer from 1 to 2;

n₂ is an integer from 1 to 2;

R₅, R₆ and R₇ are independently selected from H, halogen, —CN, —CHO,—CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂,—NH(C₁-C₆), —N—C(O)—(C₁-C₆), or —NO₂;

R₈ and R₉ are independently selected from H, halogen, —CN, —CHO, —CF₃,—OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆),—N—C(O)—(C₁-C₆), or —NO₂;

or a pharmaceutically acceptable salt form thereof.

A ninth subgroup of compounds useful in the methods of this inventioninclude those of formulae (VI) or (VII) wherein: n₁ is 1; n₂ is 1; andX₁, X₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are as defined in the eighthsubgroup, above, or a pharmaceutically acceptable salt form thereof.

A tenth subgroup useful in the methods of this invention comprises thecompounds of the ninth subgroup, above, wherein X₁ is a chemical bondand n₁, n₂, X₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ are as defined in theninth subgroup, above, or a pharmaceutically acceptable salt formthereof.

A further method of treatment of asthma of this invention comprisesadministering to a mammal in need of such treatment a pharmaceuticallyeffective amount of a compound of this invention, as described above,and a pharmaceutically effective amount of one or more additionalanti-asthma agents.

Anti-asthma agents useful with these combinations includelong-term-control medications, such as corticosteroids(glucocorticoids), cromolyn sodium (disodium cromoglycate—DSCG),nedocromil, methylxanthines (such as theophylline) and leukotrienemodifiers. Useful leukotriene modifiers include leukotriene receptorantagonists, such as zafirlukast (ACCOLATE®) and monetlukast(SINGULAIR®), and 5-lipoxygenase inhibitors, such as zileuton (ZYFLO®).Useful corticosteroids include inhaled products, such as Beclomethasonedipropionate, Budesonide, Flunisolide, Fluticasone, and Triamcinolone,as well as the pharmaceutically acceptable salt forms thereof. Alsouseful are systemic corticosteroids such as prednisone, prednisolone andmethylprednisolone.

Also useful are quick-relief anti-asthma medications, such aslong-acting beta₂-agonists, short-acting beta₂-agonists,anticholinergics and systemic corticosteroids. β-Adrenergic agents whichmay be used include epinephrine, isoproterenol, metaproterenol,terbutaline, isoetharine, albuterol, bitolterol and perbuterol. Usefulanticholinergic agents include atropine (and its derivative ipatropiumbromide) and glycopyrrolate. The compounds of this invention may also beused to treat asthma in conjunction with allergy immunotherapies, whichalso referred to in the art as hyposensitization therapies. Thesecompounds may be administered according to the dosages and regimensknown in the art.

Additional anti-asthma agents which may be used in the combinations ofthis invention include pranlukast, anakinra, seratrodast, olopatadinehydrochloride, cromoglicate lisetil, ramatroban, interleukin-4 receptor(Immunex), urodilatin, colforsin daropate, salbutamol, LCB-2183,andolast, ciclesonide, budesonide, formoterol, omalizumab, tranilast,saredutant, CDP-835 (anti-IL-5 Mab), fexofenadine HCl,N-(1-(Chlorophenyl)-1-methylethyl)-3-(imidazol-1-yl)propylaminedihydrochloride(BTS-71-321), cilomilast, bimosiamose, Corticotropin-releasing factor,clenoliximab, tiotropium bromide, 2H-1,2-Benzoselenazine,3,4-dihydro-4,4-dimethyl (BXT-51072), atreleuton, (R)-salbutamol,8-Methoxyquinoline-5-(N-(2,5-dichloropyridin-3-yl)) carboxamide(D-4418), triamcinolone acetonide, KW-4490 (KF-19514), LAX-300 (LX-109),IDEC-152 (ST-152; anti-CD23 antibody), cytokine Traps, anandamide,SRL-172, salmeterol+Fluticasone, KCA-757, 2-Pyridinecarboxylic acid,6-(2-(3,4-diethoxyphenyl)-4-thiazolyl)-(OPC-6535), PM-56D9, salbutamol,CT-2820 (PDEIV inhibitors), beclometasone, nepadutant, ketotifenfumarate, DHEAS (PB-005), Pharmaprojects No. 5163, No. 5278 and No.5297, salbutamol sulfate, EPI-2010 (EpiGenRx), mepolizumab, Benzamide,N-(5-(3-((4-chlorophenyl)sulfonyl)propyl)-2-(1H-tetrazol-5-ylmethoxy)phenyl)-3-((4-(1,1-dimethylethyl)-2-thiazolyl)methoxy)-,monosodium salt (YM-158),2-(4-ethoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydro-pyridazin-3-onePharmaprojects (No. 5450), Sch-205528, L-826141 (Pharmaprojects No.5477), Budesonide, duramycin,4,4-Bis(4-(quinolin-2-ylmethoxy)phenyl)pentanoic acid sodium salt(VML-530), IL-9 inhibitor, beclometasone dipropionate, formoterol,cyclo(MePhe-Leu-Asp-Val-D-Arg-D-Arg) (ZD-7349), salbutamol,Ethanaminium, 2-(((2-acetyl-4-((1-oxohexadecyl)amino)phenoxy)hydroxyphosphinyl)oxy)-N, N, N-trimethyl-, inner salt(CPR-2015), PD-168787 (Cl-1018), cathepsin S inhibitors, SB-240683(anti-IL-4 Mab), BIIL-284, APC-2059, budesonide+formoterol, Bay-16-9996(IL-4 antagonist), beclometasone, GW-328267, VLA-4 antagonists,4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone(TA-270), CpG-7909 (ProMune), DNK-333A (Pharmaprojects No. 6070),AWD-12-281, LM-1507 (LM-1484), formoterol, MOL-6131, cathepsin Sinhibitors, CS-615, ibudilast,2-{N-(4-(4-Chlorophenylsulfonylamino)butyl)-N-{3-(2-(4-cyclobutylthiazol-2-yl)ethyl)benzyl}sulfamoyl}benzoicacid (S-36527), and2-{N-(4-(4-Chlorophenylsulfonylamino)butyl)-N-{3-((4-isopropylthiazol-2-yl)methyloxy)benzyl}sulfamoyl}benzoicacid (S-36496).

This invention also provides pharmaceutical compositions useful in themethods herein comprising a pharmaceutically effective amount of acompound of this invention, or a pharmaceutically acceptable salt formthereof, and one or more pharmaceutically acceptable carriers orexcipients.

Compounds of the present invention may be used in a pharmaceuticalcomposition when combined with a pharmaceutically acceptable carrier.Such a composition may also contain (in addition to a compound orcompounds of the present invention and a carrier) diluents, fillers,salts, buffers, stabilizers, solubilizers, and other materials wellknown in the art. The term “pharmaceutically acceptable” means anon-toxic material that does not interfere with the effectiveness of thebiological activity of the active ingredient(s). The characteristics ofthe carrier will depend on the route of administration. Thepharmaceutical composition may further contain other anti-inflammatoryagents. Such additional factors and/or agents may be included in thepharmaceutical composition to produce a synergistic effect withcompounds of the present invention, or to minimize side effects causedby the compound of the present invention.

The pharmaceutical composition of the invention may be in the form of aliposome in which compounds of the present invention are combined, inaddition to other pharmaceutically acceptable carriers, with amphipathicagents such as lipids which exist in aggregated form as micelles,insoluble monolayers, liquid crystals, or lamellar layers in aqueoussolution. Suitable lipids for liposomal formulation include, withoutlimitation, monoglycerides, diglycerides, sulfatides, lysolecithin,phospholipids, saponin, bile acids, and the like. Preparation of suchliposomal formulations is within the level of skill in the art, asdisclosed, for example, in U.S. Pat. No. 4,235,871; U.S. Pat. No.4,501,728; U.S. Pat. No. 4,837,028; and U.S. Pat. No. 4,737,323, all ofwhich are incorporated herein by reference.

As used herein, the terms “pharmaceutically effective amount” or“therapeutically effective amount” as used herein means the total amountof each active component of the pharmaceutical composition or methodthat is sufficient to show a meaningful patient benefit, i.e.,treatment, healing, prevention, inhibition or amelioration of aphysiological response or condition, such as an inflammatory conditionor pain, or an increase in rate of treatment, healing, prevention,inhibition or amelioration of such conditions. When applied to anindividual active ingredient, administered alone, the term refers tothat ingredient alone. When applied to a combination, the term refers tocombined amounts of the active ingredients that result in thetherapeutic effect, whether administered in combination, serially orsimultaneously.

Each of the methods of treatment or use of the present invention, asdescribed herein, comprises administering to a mammal in need of suchtreatment or use a pharmaceutically or therapeutically effective amountof a compound of the present invention, or a pharmaceutically acceptablesalt form thereof. Compounds of the present invention may beadministered in accordance with the method of the invention either aloneor in combination with other therapies such as treatments employingother anti-inflammatory agents, cytokines, lymphokines or otherhematopoietic factors. When co-administered with one or more otheranti-inflammatory agents, cytokines, lymphokines or other hematopoieticfactors, compounds of the present invention may be administered eithersimultaneously with the other anti-inflammatory agent(s), cytokine(s),lymphokine(s), other hematopoietic factor(s), thrombolytic oranti-thrombotic factors, or sequentially. If administered sequentially,the attending physician will decide on the appropriate sequence ofadministering compounds of the present invention in combination withother anti-inflammatory agent(s), cytokine(s), lymphokine(s), otherhematopoietic factor(s), thrombolytic or anti-thrombotic factors.

Administration of compounds of the present invention used in thepharmaceutical composition or to practice the method of the presentinvention can be carried out in a variety of conventional ways, such asoral ingestion, inhalation, or cutaneous, subcutaneous, or intravenousinjection.

When a therapeutically effective amount of compounds of the presentinvention is administered orally, compounds of the present inventionwill be in the form of a tablet, capsule, powder, solution or elixir.When administered in tablet form, the pharmaceutical composition of theinvention may additionally contain a solid carrier such as a gelatin oran adjuvant. The tablet, capsule, and powder contain from about 5 to 95%compound of the present invention, and preferably from about 25 to 90%compound of the present invention. When administered in liquid form, aliquid carrier such as water, petroleum, oils of animal or plant originsuch as peanut oil, mineral oils, phospholipids, tweens, triglycerides,including medium chain triglycerides, soybean oil, or sesame oil, orsynthetic oils may be added. The liquid form of the pharmaceuticalcomposition may further contain physiological saline solution, dextroseor other saccharide solution, or glycols such as ethylene glycol,propylene glycol or polyethylene glycol. When administered in liquidform, the pharmaceutical composition contains from about 0.5 to 90% byweight of compound of the present invention, and preferably from about 1to 50% compound of the present invention.

When a therapeutically effective amount of compounds of the presentinvention is administered by intravenous, cutaneous or subcutaneousinjection, compounds of the present invention will be in the form of apyrogen-free, parenterally acceptable aqueous solution. The preparationof such parenterally acceptable protein solutions, having due regard topH, isotonicity, stability, and the like, is within the skill in theart. A preferred pharmaceutical composition for intravenous, cutaneous,or subcutaneous injection should contain, in addition to compounds ofthe present invention, an isotonic vehicle such as Sodium ChlorideInjection, Ringer's Injection, Dextrose Injection, Dextrose and SodiumChloride Injection, Lactated Ringer's Injection, or other vehicle asknown in the art. The pharmaceutical composition of the presentinvention may also contain stabilizers, preservatives, buffers,antioxidants, or other additives known to those of skill in the art.

The amount of compound(s) of the present invention in the pharmaceuticalcomposition of the present invention will depend upon the nature andseverity of the condition being treated, and on the nature of priortreatments the patient has undergone. Ultimately, the attendingphysician will decide the amount of compound of the present inventionwith which to treat each individual patient. Initially, the attendingphysician will administer low doses of compound of the present inventionand observe the patient's response. Larger doses of compounds of thepresent invention may be administered until the optimal therapeuticeffect is obtained for the patient, and at that point the dosage is notincreased further. It is contemplated that the various pharmaceuticalcompositions used to practice the method of the present invention shouldcontain about 0.1 μg to about 100 mg (preferably about 0.1 mg to about50 mg, more preferably about 1 mg to about 2 mg) of compound of thepresent invention per kg body weight.

The duration of intravenous therapy using the pharmaceutical compositionof the present invention will vary, depending on the severity of thedisease being treated and the condition and potential idiosyncraticresponse of each individual patient. It is contemplated that theduration of each application of the compounds of the present inventionwill be in the range of 12 to 24 hours of continuous intravenousadministration. Ultimately the attending physician will decide on theappropriate duration of intravenous therapy using the pharmaceuticalcomposition of the present invention.

A preferred lipid based oral formulation of this invention has beenprepared by blending 50% PHOSOL® 53MCT (American Lecithin Company), 5%Polysorbate 80, 15% LABRASOL® Caprylocaproyl macrogol-8 glycerides(Gattefosse Corp.), 15% Propylene Carbonate and 15% active cPLA2inhibiting compound(s) of this invention, each percentage listed beingby weight.

This invention can be further understood by the following non-limitingspecific examples.

Method A

The initial indole of Method A may be alkylated at the C3 position (thecarbon atom at the 3-position of the indole moiety) with aldehydes orthe corresponding acetals in the presence of a Lewis or Bronsted acid,such as boron triflouride etherate or trifluoroacetic acid. The indolenitrogen may then be alkylated by treatment with a strong base such assodium bis(trimethylsilyl) amide, n-BuLi, sodium hydride or potassiumhydride in a solvent such as DMF, DMSO or THF followed by exposure tothe appropriate alkyl halide. The resulting product can be treated withcarbon tetrabromide in carbon tetrachloride and a catalytic amount ofbenzoyl peroxide to effect dibromination of the C2 methyl group. Thedibromide can then either be stirred with silver carbonate in acetonewater or poured into DMSO and stirred. Both of these procedures generatethe aldehyde which is then subjected to the nitro aldol reaction withnitromethane and a catalytic amount of ammonium acetate at reflux. Theresulting vinyl nitro intermediate is reduced to the amine upontreatment with zinc mercury amalgam in a mixture of THF and conc. HCL atreflux. This amine can then be treated with the requisite sulfonylchloride under biphasic conditions, aqueous sodiumbicarbonate/dichloromethane, or in organic solvent with the addition ofa hindered organic amine base. The final hydrolysis was accomplishedunder basic conditions with sodium hydroxide in water and methanol andTHF at room temperature or at elevated temperature. Alternatively it maybe cleaved by treatment with sodium thiomethoxide in a solvent such asTHF or DMF at elevated temperatures (50° C.-100° C.). This method wasused in the synthesis of Examples 1-88, 108-112, and 126-128.

Method B

The initial halide of Method B is refluxed in aqueous sodium sulfite anda suitable cosolvent if necessary, such as alcohol, dioxane etc, for therequired amount of time to form the desired sodium sulfonate. Thisintermediate was treated with thionyl chloride, phosphorouspentachloride or oxalyl chloride, in dichloromethane with a small amountof DMF and stirred for several hours at room temperature until thesulfonyl chloride is formed. The thus formed sulfonyl chloride is thenused crude in Method A. This method was used in the synthesis ofExamples 1-88, 108-112 and 126-128 when the sulfonyl chloride was notcommercially available.

EXAMPLE 14-[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

This synthesis is depicted in Method A.

Step 1: To 4-hydroxy-benzoic acid methyl ester (1.0 eq) in DMF (0.83 M)was added K₂CO₃ (2.0 eq) followed by 2-bromo-1,1-diethoxy-ethane and thereaction mixture was stirred at 110° C. for 2 days. TLC showed a newspot. The reaction mixture was diluted with ethyl acetate, washed with1N NaOH, water, and brine, dried over sodium sulfate, and solvent wasremoved to afford desired product in 84% yield. This material was usedin the next step without further purification.

Step 2: To the above product (1.0 eq) and 5-chloro-2-methyl indole (1.0eq) in CH₂Cl₂ (0.12 M) was added triethylsilane (3.0 eq) followed bytrifluoroacetic acid (3.0 eq). After being stirred overnight at roomtemperature, added water and trifluroacetic acid (1.0 eq) to thereaction mixture, stirred at room temperature for two days, diluted withCH₂Cl₂, washed with 1N NaOH, water, brine, dried over sodium sulfate.Trituration of the material with CH₂Cl₂ and hexanes afforded the C3alkylated indole in 92% yield

Step 3: To the indole from above (1.0 eq) in DMF (0.36 M) at 25° C. wasadded NaH (1.2 eq, 60% dispersion in oil), and the brown solution wasstirred at 0 to −5° C. for 1 h and then compound bromodiphenylmethanewas added (1.1 eq), and then the reaction mixture was stirred overnight.It was then quenched with water, diluted with ethyl acetate, washed withwater and brine, dried over sodium sulfate and purified by columnchromatography to yield 72% of the desired product.

Step 4: To the N-alkylated indole from above (1.0 eq) in CCl₄ (0.2 M)was added N-bromosuccinimide (2.0 eq) and a catalytic amount of benzoylperoxide. The solution was heated to reflux for 3 h, cooled to 25° C.,filtered, and the solid was washed with CCl₄. The filtrate wasconcentrated to a foam, which was dried. The foam was dissolved inacetone, and Ag₂CO₃ (1.1 eq.) was added followed by water and thereaction mixture was stirred overnight at room temperature. It wasfiltered and washed with acetone. The filtrate was concentrated to aresidue, to which was added water. This mixture was extracted with ethylacetate, washed with brine, dried over sodium sulfate and thenchromatographic purification on the residue gave the desired product in85% yield. Alternatively the dibromide from the reaction with NBS couldbe poured into DMSO (10-20% concentration by weight) stirred for 30minutes at room temperature. When the reaction was deemed complete itwas poured into water and the resulting precipitate was isolated byfiltration, the cake was washed with water and dried to yield anessentially quantitative yield.

Step 5: To the above aldehyde (1.0 equiv) in CH₃NO₂ (0.2 M) was addedammonium acetate (4 equiv) and the resulting mixture was heated toreflux for 4 h. The reaction mixture was then diluted with EtOAc andwashed with brine. The aqueous phase was extracted with EtOAc. Thecombined organic extracts were washed with brine, dried over sodiumsulfate, and concentrated until an orange crystalline solidprecipitated. The mixture was refrigerated overnight and the nitroolefin(76% yield) was collected by filtration. Evaporation of the solutionphase and purification of the residue by column chromatography (gradientelution 100% toluene→1% EtOAc-toluene) afforded an additional amount ofthe nitroolefin (23% yield).

Step 6: Zinc dust (20 equiv) was suspended in 5% aqueous HCl solution (8M Zn/5% HCl). To this mixture was added HgCl₂ (0.28 equiv). The mixturewas shaken for 10 min, the aqueous phase was decanted and replaced withfresh 5% HCl, and again the mixture was shaken for 5 min and the aqueousphase was removed. The zinc-mercury amalgam thus generated was thenadded to a mixture of the nitroolefin (1.0 equiv) and conc. HCl (80equiv) in THF (0.04 M nitroolefin/THF). The mixture was maintained at agentle reflux for 1 h. The formation of product was followed by TLCanalysis. The mixture was cooled to room temperature and the solids wereremoved by filtration through Celite. Conc. NH₄OH was added to thesolution phase and the mixture was concentrated on the rotaryevaporator. The residue was dissolved in CH₂Cl₂ and conc. NH₄OH. Theaqueous phase was extracted with CH₂Cl₂, and the organic phase waswashed with brine, dried over sodium sulfate, and concentrated.Purification by column chromatography afforded the desired product (65%yield).

Step 7: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(1.0 equiv) and sat. NaHCO₃ (0.14 M) in CH₂Cl₂ (0.07 M) was addedα-toluenesulfonyl chloride (1.0 equiv). After 1 h the mixture was pouredinto saturated sodium bicarbonate and extracted with CH₂Cl₂. Thecombined organic phase was washed with brine, dried over sodium sulfateand purified by column chromatography (gradient elution using 20%EtOAc-hexanes→50% EtOAc-hexanes) to afford 86% of the desired product.

Step 8: The resulting ester was hydrolyzed by stirring with 1N NaOH (5equiv) in THF (0.07 M) and enough MeOH to produce a clear solution. Thereaction was monitored by TLC (10% MeOH—CH₂Cl₂) for the disappearance ofstarting material. The mixture was heated in a 60 degrees C. oil bathfor 2 hour. The mixture was concentrated, diluted with H₂O, andacidified to pH 2-4 using 1 M HCl. The aqueous phase was extracted withEtOAc and the organic phase was washed with brine, dried over sodiumsulfate, and concentrated to afford the desired product in 92% yield.HRMS calc for [C₃₉H.₃₅ClN₂O₅.S+H] 679.2028 found 679.2031.

EXAMPLE 24-[2-(1-Benzhydryl-5-chloro-2-{2-[(isopropylsulfonyl)-amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and isopropylsulfonyl chloride according to theprocedure in Example 1 Step 7 in 55% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. HRMS calc for[C₃₅H.₃₅ClN₂O₅.S+H] 631.2028 found 631.2029.

EXAMPLE 34-[2-(1-Benzhydryl-2-{2-[(butylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 1-butanesulfonyl chloride according to theprocedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₆H.₃₇ClN₂O₅.S+H] 645.2185 found 645.2185.

EXAMPLE 44-{2-[1-Benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) (1.0 equiv) and Et₃N (3.0 equiv) or pyridine (3.0equiv) in CH₂Cl₂ (0.05 M) was added 1-methylimidazole-4-sulfonylchloride (1.2 equiv). The reaction was monitored by TLC (10%MeOH—CH₂Cl₂) and was heated if necessary. After 30 min the mixture waspoured into saturated sodium bicarbonate and extracted with CH₂Cl₂. Thecombined organic phase was washed with brine, dried over sodium sulfateand purified by column chromatography to afford 92% of the desiredproduct.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₃₆H.₃₃ClN₄O₅.S+H] 669.1933 found 669.1932.

EXAMPLE 54-{2-[1-Benzhydryl-2-(2-{[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-bromo-2-chloropyridine-5-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 74% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calc for[C₃₇H.₃₀BrCl₂N₃O₅.S+H] 778.0539 found 778.0544.

EXAMPLE 64-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and (1R)(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 77% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₄₂H₄₃ClN₂O₆.S+H] 739.2603 found 739.26.

EXAMPLE 74-(2-{1-Benzhydryl-5-chloro-2-[2-({[(methylsulfonyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and (methanesulfonyl)methanesulfonyl chlorideaccording to the procedure in Example 4 Step 1 in 43% yield.

Step 2: The ester intermediate was hydrolyzed according to Example 117Step 2 to afford the title acid in 95% yield. HRMS calc for[C₃₄H₃₃ClN₂O₇.S₂+H] 681.1491 found 681.1489.

EXAMPLE 84-(2-{1-Benzhydryl-5-chloro-2-[2-({[2-(1-naphthyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-(1-naphthyl)ethanesulfonyl chloride accordingto the procedure Example 1 Step 7 in 60% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₄H₃₉ClN₂O₅.S+H] 743.2341 found 743.2338.

EXAMPLE 94-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-nitro-α-toluenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 82% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. HRMS calc for[C₃₉H₃₄ClN₃O₇.S+H] 724.1879 found 724.1877.

EXAMPLE 104-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and [(3,4-dichlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 82% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅.S+H] 747.1249 found 747.1249.

EXAMPLE 114-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and [(3,5-dichlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 100% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅.S+H] 747.1249 found 747.1249.

EXAMPLE 124-(2-{1-Benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)-benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and [[3-(trifluoromethyl)-phenyl]methyl]sulfonylchloride according to the procedure in Example 1 Step 7 in 74% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₅S+H] 747.1902 found 747.1904.

EXAMPLE 134-(2-{1-Benzhydryl-5-chloro-2-[2-({[(4-(trifluoromethyl)-benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and [[4-(trifluoromethyl)phenyl]methyl]sulfonylchloride according to the procedure in Example 1 Step 7 in 77% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 83% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₅S+H] 747.1902 found 747.1901.

EXAMPLE 144-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)-sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and [(4-fluorophenyl)methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 Step 1 in 86% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₉H₃₄ClFN₂O₅S+H] 697.1934 found 697.1938.

EXAMPLE 154-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and [(4-chlorophenyl-)methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 73% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂O₅S+H] 713.1638 found 713.1643.

EXAMPLE 164-{2-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-{2-[2-nitrobenzyl]benzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate,Example 9, step 1, (1.0 equiv) in CH₂Cl₂ (0.014 M) was added a mixtureof tin(II) chloride dihydrate (3.0 equiv) dissolved in concentrated HCl.After 16 h the mixture was basified (pH 10) with 3 N NaOH and extractedwith CH₂Cl₂. The combined organic phase was washed with brine, driedover sodium sulfate and purified by column chromatography (gradientelution using 20% EtOAc-hexanes→50% EtOAc-hexanes) to afford 83% of thedesired product.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 83% yield. HRMS calc for[C₃₉H₃₆ClN₃O₅S+H] 694.2137 found 694.2136.

EXAMPLE 174-{2-[1-Benzhydryl-5-chloro-2-(2-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and dimethylsulfamoyl chloride according to theprocedure in Example 1 Step 7 in 49% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1to afford the title acid in 95% yield. HRMS calc for[C₃₄H₃₄ClN₃O₅S+H] 632.1981 found 632.1984.

EXAMPLE 184-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-difluorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To 3,4-difluorobenzyl bromide (1.0 equiv) in H₂O (0.74 M) wasadded sodium sulfite (1.1 equiv). The mixture was heated to reflux for16 hours then cooled to room temperature. The white precipitate wasfiltered and dried to afford 95% of the sodium sulfonate intermediate.

Step 2: To 3,4-difluorobenzyl sodium sulfonate (7.6 equiv) in CH₂Cl₂(0.76 M) was added DMF (5.6 equiv) and SOCl₂ (30 equiv). After 1 h themixture was concentrated and azeotroped with toluene. The residue wassuspended in CH₂Cl₂ (0.38 M) and methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) (1.0 equiv) and sat. NaHCO₃ (0.76 M) were added.After 1 h the mixture was poured into H₂O and extracted with CH₂Cl₂. Thecombined organic phase was washed with brine, dried over sodium sulfateand purified by column chromatography (gradient elution using 20%EtOAc-hexanes→40% EtOAc-hexanes) to afford 94% of the methyl esterintermediate.

Step 3: The methyl ester was hydrolyzed according to Step 8 Example 1 toafford the title acid in 93% yield. HRMS calc for [C₃₉H₃₃ClF₂N₂O₅S+H]715.184 found 715.1843.

EXAMPLE 194-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-naphthylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2-(bromomethyl)naphthalene according to the procedure in Example 18 Step1-2 in 34% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in58% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 74% yield. HRMS calc for[C₄₃H₃₇ClN₂O₅S+H] 729.2185 found 729.2189.

EXAMPLE 203-({[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}methyl)benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from methyl3-(bromomethyl)benzoate according to the procedure in Example 18 Step1-2.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6 Example 1) according to the procedure in Example 1 Step 7 in 23%yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 93% yield. HRMS calc for[C₄₀H₃₅ClN₂O₇S+H] 723.1926 found 723.1932

EXAMPLE 214-(2-{1-benzhydryl-5-chloro-2-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)ethyl]1H-indol-3-yl}ethoxy)benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 2-phenyl-ethenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 66%yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 98% yield. HRMS calc for [C₄₀H₃₅ClN₂O₅S+H]691.2028 found 691.2034.

EXAMPLE 224-{2-[1-benzhydryl-5-chloro-2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added trifluoromethylsulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 49%yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 100% yield. HRMS calc for[C₃₃H₂₈ClF₃N₂O₅S+H] 657.1432 found 657.1435.

EXAMPLE 234-[2-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added cyclopropanesulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 75% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 84% yield. HRMS calc for [C₃₅H₃₃ClN₂O₅S+H]629.1872 found 629.1874.

EXAMPLE 244-(2-{1-benzhydryl-2-[2-({[3,5-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 3,5-bis(trifluoromethyl)benzylsulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 79% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 81% yield. HRMS calc for[C₄₁H₃₃ClF₆N₂O₅S+H] 815.1776 found 815.1776.

EXAMPLE 252-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added methyl (2-chlorosulfonyl)benzoateaccording to the procedure in Example 1 Step 7 to generate the productin 100% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 61% yield. HRMS calc for [C₃₉H₃₃ClN₂O₇S+H]709.177 found 709.1772.

EXAMPLE 264-[2-(1-benzhydryl-5-chloro-2-{2-[(2-naphthylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 2-naphthalenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 53%yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₃₅ClN₂O₅S+H] 715.2028 found 715.2034.

EXAMPLE 274-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 3,5-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 60% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 88% yield. HRMS calc for[C₃₈H₃₁Cl₃N₂O₅S+H] 733.1092 found 733.1096.

EXAMPLE 284-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 3,4-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 60% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 80% yield. HRMS calc for[C₃₈H₃₁Cl₃N₂O₅S+H] 733.1092 found 733.1094.

EXAMPLE 294-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}ethyl)-1Hindol-3-yl]ethoxy}benzoic acid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added [(2,3-dichlorophenyl)-methyl]sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 50% yield.

Step 2—The resulting ester was hydrolyzed by stirring with KOH (67 mg, 5equiv.) in THF (5 mL) MeOH (5 mL) and H₂O (2 mL). The reaction wasmonitored by TLC (10% MeOH—CH₂Cl₂) for the disappearance of startingmaterial. The mixture was stirred overnight at room temperature and thenconcentrated, diluted with H₂O, and acidified to pH 2-4 using 1 M HCl.The aqueous phase was extracted with EtOAc and the organic phase waswashed with brine, dried over sodium sulfate, and concentrated to affordthe desired product in 98% yield. HRMS calc for [C₃₉H₃₃Cl₃N₂O₅S+H]747.1249 found 747.1254.

EXAMPLE 304-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added [(2,4-dichlorophenyl)-methyl]sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 98% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 2 Example29 to afford the title acid in 90% yield. HRMS calc for [C₃₉H₃₃Cl₃N₂O₅S+H] 747.1249 found 747.1255.

EXAMPLE 31 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-chloro-phenylmethanesulfonylamino)-ethyl]-1Hindol-3-yl}-ethoxy)-benzoic acid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added [(2-chlorophenyl)-methyl]sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 86% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 2 Example29 to afford the title acid in 90% yield. HRMS calc for [C₃₉H₃₄Cl₂N₂O₅S+H] 713.1638 found 713.1644.

EXAMPLE 324-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added (4-chloro-2-nitro-phenyl)-methanesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 74% yield.

Step 2—The ester intermediate was hydrolyzed according to Step 2 Example29 to afford the title acid in 90% yield. HRMS calc for [C₃₉H₃₃Cl₂N₃O₇S+H] 758.1489 found 758.1494.

The acid resulting from Method A, or any subsequent method could be usedas a subtrate for palladium catalyzed amination reaction using a base,an amine, a phosphine ligand and palladium reagent.

EXAMPLE 334-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-morpholin-4-yl-1H-indol-′3-yl)ethoxy]benzoicacid4-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-morpholin-4-yl-1H-indol-3-yl)ethoxy]benzoicacid

Step 1—A flask was charged with tris(dibenzylideneacetone)dipalladium(0)(0.01 eq.), 2-(di-t-butylphosphino)biphenyl (0.04 eq.), sodiumt-butoxide (2.4 eq.) and the acid from Example 1 step 8 (1.0 eq.). 1.5ml toluene (1.0 M) was added to the flask followed by morpholine (1.2eq.) The reaction was heated to reflux for five hours. The reactionmixture was partitioned between 5% hydrochloric acid and dietheyl ether.The organic layer was washed with distilled water, followed by brine,dried over sodium sulfate and concentrated. The product was purified bypreparatory LC-MS to afford 7.8% of the desired product. HRMS calc for[C₄₃H₄₃N₃O₆S+H] 730.2945 found 730.2945.

EXAMPLE 344-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: (2-Cyano-phenyl)-methanesulfonyl chloride was prepared accordingto Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(2-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7as a white solid in 72% yield.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Exampleto afford the title acid in 74% yield. MS (ES) m/z (M−1) 702.0; HRMSCalcd. for C₄₀H₃₅ClN₃O₅S (M+1): 704.1980. Found: 704.1984. Anal. Calcd.for C₄₀H₃₄ClN₃O₅S: C, 68.22; H, 4.87; N, 5.97. Found: C, 67.92; H, 5.11;N, 5.54.

EXAMPLE 354-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-difluorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3,5-difluorobenzyl bromide according to the procedure in Example 18 Step1-2 in 95% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in78% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 83% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂ O₅S+H] 715.184 found 715.1842.

EXAMPLE 364-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-cyanobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: (3-Cyano-phenyl)-methanesulfonyl chloride was prepared accordingto Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(3-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 81% yield. MS (ES) m/z (M−1) 702.1; HRMSCalcd. for C₄₀H₃₃ClN₃O₅S (M−1): 702.1834. Found: 702.1833. Anal. Calcd.for C₄₀H₃₄ClN₃O₅S.0.8H₂O: C, 67.00; H, 5.00; N, 5.86. Found: C, 67.22;H, 5.19; N, 5.44.

EXAMPLE 374-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-cyanobenzyl-)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1(4-Cyano-phenyl)-methanesulfonyl chloride was prepared accordingto Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1)and(4-cyano-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 77% yield.MS (ES) m/z (M−1) 702.1; HRMSCalcd. for C₄₀H₃₅ClN₃O₅S (M+1): 704.1980. Found: 704.1981. Anal. Calcd.for C₄₀H₃₄ClN₃O₅S: C, 68.22; H, 4.87; N, 5.97. Found: C, 68.09; H, 4.97;N, 5.73.

EXAMPLE 384-(2-{1-Benzhydryl-5-chloro-2-[2-({[4-(1piperidinyl-sulfonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1:[4-(Piperidine-1-sulfonyl)-phenyl]-methanesulfonyl chloride wasprepared according to Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and4-(Piperidine-1-sulfonyl)-phenyl]-methanesulfonyl according to Example 1Step 7.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 73% yield. MS (ES) m/z (M−1) 824.2; HRMSCalcd. for C₄₄H₄₃ClN₃O₇S₂ (M−1):824.2236. Found: 824.2246. Anal. Calcd.for C₄₄H₄₄ClN₃O₇S₂.0.5H₂O: C, 63.25; H, 5.43; N, 5.03. Found: C, 62.85;H, 5.64; N, 4.64.

EXAMPLE 394-(2-{2-[2-({[4-(Aminosulfonyl)benzyl]sulfonyl}-amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: (4-Sulfamoyl-phenyl)-methanesulfonyl chloride was preparedaccording to Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(4-Sulfamoyl-phenyl)-methanesulfonyl chloride according to Example 1Step 7.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 69% yield. MS (ES) m/z (M−1) 755.9; HRMSCalcd. for C₃₉H₃₅ClN₃O₇S₂ (M−1): 756.1613. Found: 756.1612. Anal. Calcd.for C₃₉H₃₆ClN₃O₇S₂: C, 61.77; H, 4.79; N, 5.54. Found: C, 61.93; H,5.12; N, 5.19.

EXAMPLE 404-(2-{1-Benzhydryl-5-chloro-2-[2-(4-methanesulfonyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: (4-Methanesulfonyl-phenyl)-methanesulfonyl chloride was preparedaccording to Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1)((4-Methanesulfonyl-phenyl)-methanesulfonyl chloride according toExample 1 Step 7.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 75% yield. MS (ES) m/z (M−1) 755.0; HRMSCalcd. for C₄₀H₃₈ClN₂O₇S₂ (M+1): 757.1804. Found: 757.1804. Anal. Calcd.for C₄₀H₃₇ClN₂O₇S₂.H₂O: C, 61.96; H, 5.07; N, 3.61. Found: C, 61.82; H,5.10; N, 3.48.

EXAMPLE 414(2-{1-Benzhydryl-5-chloro-2-[2-(4-diethylsulfamoyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: (4-Diethylsulfamoyl-phenyl)-methanesulfonyl chloride wasprepared according to Example 18 Step 1-2 (crude yield 100%).

Step 2: The title compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 6, Example 1) and(4-Diethylsulfamoyl-phenyl)-methanesulfonyl chloride according toExample 1 Step 7.

Step 3—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 66% yield. MS (ES) m/z (M−1) 812.1; HRMSCalcd. for C₄₃H₄₅ClN₃O₇S₂ (M+1): 814.2382. Found: 814.2385. Anal. Calcd.for C₄₃H₄₄ClN₃O₇S₂.0.3H₂O: C, 62.99; H, 5.48; N, 5.14. Found: C, 62.91;H, 5.67; N, 4.79.

EXAMPLE 424-{3-[1-Benzhydryl-5-chloro-2-(2-phenylmethane-sulfonylamino-ethyl)-1H-indol-3-yl]-propyl}-benzoicacid

Step 1: A mixture of methyl-4-iodobenzoate (5.3 g, 20.2 mmol), allylalcohol (1.78 g, 30.3 mmol), NaHCO₃ (4.24 g, 50.5 mmol), Pd(OAc)₂ (0.14g, 0.60 mmol), (n-Bu)₄NBr (6.55 g, 20.2 mmol) and 4-A molecular Sieves(4.1 g) in anhydrous DMF (69 mL) was stirred at room temperature for 4days. The reaction mixture was filtered through celite and the filtratepoured onto water and extracted with EtOAc. Organic layer was washedwith brine, dried (Na₂SO₄), and concentrated under vacuum. Flashchromatography (silica gel, 10-20% EtOAc-hexanes) gave 2.11 g (85% basedon the recovered starting material) of the desired4-(3-Oxo-propyl)-benzoic acid methyl ester as a clear oil.

Step 2: To a solution of 5-chloro-2-methylindole (0.86 g, 5.2 mmol) and4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) inmethylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol), followedby triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirredovernight, quenched with sat. NaHCO₃ solution (50 mL), and the organiclayer was washed with sat. NaHCO₃ solution, water, brine, and dried(Na₂SO₄). Solvent was removed under reduced pressure, and the residuewas purified by flash column chromatography with 10-20% EtOAc/hexanes toyield the desired product in 94% (1.67 g) yield.

Step 3: To a solution of the product from step 2 (1.66 g, 4.86 mmol) inDMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) underN₂ atmosphere. The mixture was stirred for 1 h at room temperature,followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29mmol) in DMF (5 mL). This reaction mixture was stirred overnight at roomtemperature. Water (500 mL) was added to reaction mixture, it wasextracted with EtOAc, washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure to a brown syrup, which was purifiedby silica-gel chromatography using 10% EtOAc/hexanes as eluent toisolate 4 as a white solid in 59% (1.47 g) yield.

Step 4: The product from above (1.46 g, 2.87 mmol) was dissolved in CCl₄(14.5 mL), followed by the addition of NBS (1.02 g, 5.73 mmol) andbenzoyl peroxide (2 mg). The reaction mixture was heated to reflux for 1h (until all the starting material disappeared). This mixture was cooledto room temperature, filtered and the solid was washed with CCl₄. Thefiltrate was evaporated to a brown residue, which was dissolved inacetone (40 mL) and water (4 mL), Ag₂CO₃ (1.75 g, 3.16 mmol) was thenadded to this solution and after being stirred overnight at roomtemperature, it was filtered through celite, the solvent was evaporatedunder reduced pressure, and water was added to the residue. It wasextracted with EtOAc, washed with brine, dried (Na₂SO₄), and evaporatedto a syrup, which was purified by 10% EtOAc/hexanes to isolate the2-formyl indole (1.13 g) in 75% yield. Alternatively the dibromide fromthe reaction with NBS could be poured into DMSO (10-20% concentration byweight) and stirred for 30 minutes at room temperature. When thereaction was deemed complete it was poured into water and the resultingprecipitate was isolated by filtration, the cake was washed with waterand dried to yield an essentially quantitative yield.

Step 5: To a solution of the 2 formyl indole from above (0.52 g, 1 mmol)in CH₃NO₂ (6.2 mL) was added NH₄OAC (0.077 g, 1 mmol), the mixture washeated to reflux for 1 h, NH₄OAc (0.077 g, 1 mmol) was then added,heating at reflux was continued for an additional 1 h, NH₄Oac (0.077 g,1 mmol) was added again and the heating continued for further 1 h. Thereaction mixture was allowed to attain room temperature, EtOAc (50 mL)was added, followed by the addition of 100 mL water. The aqueous layerwas extracted with EtOAc, and the combined organic layers were washedwith brine, dried (Na₂SO₄), and evaporated to a yellow foam, which wassubjected to chromatographic purification using 10% EtOAc/hexanes as aneluent to yield 6 as a yellow foam in 68% yield (0.38 g).

Step 6: Zn(Hg) was made by adding HgCl₂ (3.4 g, 7.2 mmol) to a mixtureof Zn-dust (34.68 g, 530.35 mmol) and 5% HCl (38 mL) in a 100 mL beaker,this mixture was stirred vigorously for 10 min. Aqueous phase wasdecanted and added 38 mL of 5% HCl again and the mixture was stirred for10 min. Aqueous phase was decanted. This solid was added to the vinylnitro compound 6 (15 g, 26.57 mmol) in THF (660 mL) and conc. HCl (64.5mL). This mixture was stirred at room temperature for 1 h, then atreflux for 15 min. The reaction mixture was cooled to room temperatureand filtered through celite. Aq. NH₄OH solution (200 mL) was added tothe filtrate, stirred for 15 min and THF was removed under reducedpressure. The aqueous layer was extracted with CH₂Cl₂, combined organiclayer was washed with brine, dried (Na2SO4) and concentrated to a brownfoam, which was purified by column chromatography by eluting the columnwith CHCl₃ in the beginning to remove non-polar impurities then with 2%MeOH/CHCl₃ to isolate the desired amine in 46% yield (6.1 g)

Step 7: To the amine(1.0 equiv.) and sat. NaHCO₃ (0.14 M) in CH₂Cl₂(0.07 M) was added α-toluenesulfonyl chloride (1.0 equiv.). After 1 hthe mixture was poured into saturated sodium bicarbonate and extractedwith CH₂Cl₂. The combined organic phase was washed with brine, driedover sodium sulfate and purified by column chromatography to afford 84%of the desired product.

Step 8: The resulting ester was hydrolyzed by stirring with 1N NaOH (5equiv.) in THF (0.07 M) and enough MeOH to produce a clear solution. Thereaction was monitored by TLC (10% MeOH—CH₂Cl₂) for the disappearance ofstarting material. The mixture was stirred overnight at room temperatureand then. concentrated, diluted with H₂O, and acidified to pH 2-4 using1 M HCl. The aqueous phase was extracted with EtOAc and the organicphase was washed with brine, dried over sodium sulfate, and concentratedto afford the desired product in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₄S+H] 677.2235 found 677.224.

EXAMPLE 434-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: This compound was prepared from the intermediate in Example 42step 6 and [(3,5-dichlorophenyl)-methyl]sulfonyl chloride according tothe procedure in Example 43 Step 7 which yielded 98% of the desiredproduct.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₅Cl₃N₂O₄S+H] 745.1456 found 745.1458.

EXAMPLE 444-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: This compound was prepared from the intermediate in Example 42step 6 and ([3,4-dichlorophenyl)-methyl]sulfonyl chloride according tothe procedure in Example 43 Step 7 which yielded 96% of the desiredproduct.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. HRMS calc for[C₄₀H₃₅Cl₃N₂O₄S+H] 745.1456 found 745.1458.

EXAMPLE 454-{2-[1-benzhydryl-5-chloro-2-(2-[(methylsulfonyl)amino]ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added methanesulfonyl chloride according to theprocedure in Example 4 Step 1 to generate the product in 92% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₃H₃₁ClN₂O₅S+H] 603.1715 found 603.1717.

EXAMPLE 464-{2-[1-benzhydryl-5-chloro-2-{2-[(phenylsulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added benzenesulfonyl chloride according to theprocedure in Example 4 Step 1 to generate the product in 90% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₈H₃₃ClN₂O₅S+H] 665.1872 found 665.1869

EXAMPLE 474-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added {[3-(trifluoromethyl)phenyl]methyl}sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 74% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₅S+H] 747.1902 found 747.1904

EXAMPLE 482-{[(2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}ethyl)amino]carbonyl}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added 2-phthalimidoethanesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 78% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₄₂H₃₈ClN₃O₈S+H] 780.2141 found 780.2148

EXAMPLE 494-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-3-ylmethylsulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added (3-pyridylmethyl)sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 52% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₈H₃₄ClN₃O₅S−H] 678.18349 found 678.18277.

EXAMPLE 504-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-4-ylmethylsulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added (4-pyridylmethyl)sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 57% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (−1) HRMS calc for[C₃₈H₃₄ClN₃O₅−H] 678.18349 found 678.18249

EXAMPLE 514-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-2-ylmethylsulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1)was added (2-pyridylmethyl)sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 42% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 56% yield. HRMS calc for[C₃₈H₃₄ClN₃O₅S−H] 678.18349 found 678.18312

EXAMPLE 524-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2,6-dimethylbenzyl chloride according to the procedure in Example 18Step 1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride and theintermediate in Example 42 step 6 according to the procedure in Example42 Step 7 in 30% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₄₁ClN₂O₄S−H] 703.24028 found 703.23973

EXAMPLE 534-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyclohexylmethyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from(bromomethyl)cyclohexane according to the procedure in Example 18 Step1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in20% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 73% yield. HRMS calc for[C₃₉H₄₁ClN₂O₅S−H] 683.23519 found 683.23474

EXAMPLE 544-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from4-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2in 95% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in80% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 90% yield. HRMS calc for[C₃₉H₃₄ClN₃O₇S+H] 724.1879 found 724.1884.

EXAMPLE 554-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2in 95% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in85% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 85% yield. HRMS calc for[C₃₉H₃₄ClN₃O₇S+H] 724.1879 found 724.1885.

EXAMPLE 56:4-{3-[5-Chloro-1-(Diphenylmethyl)-2(2-{[(2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-nitro-α-toluenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₆ClN₃O₆S+H] 722.2086 found 722.2088.

EXAMPLE 574-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and (4-Fluoro-phenyl)-methanesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 77% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 68% yield. HRMS calc for[C₄₀H₃₆ClFN₂O₄S+H] 695.2141 found 695.2145.

EXAMPLE 584-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and(4-Trifluoromethyl-phenyl)-methanesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 50% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₁H₃₆ClF₃N₂O₄S+H] 745.2109 found 745.2114.

EXAMPLE 594-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and(3-Trifluoromethyl-phenyl)-methanesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 56% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield. HRMS calc for[C₄₁H₃₆ClF₃N₂O₄S+H] 745.2109 found 745.211.

EXAMPLE 604-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and (4-chlorophenyl)-methanesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 74% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 79% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S+H] 711.1846 found 711.1847.

EXAMPLE 614-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added pyridin-2-yl-methanesulfonyl chlorideaccording to the procedure in Example 4 Step 1 to generate the productin 75% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S+H] 678.2188 found 678.2187.

EXAMPLE 624-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added pyridin-3-yl-methanesulfonyl chloridechloride according to the procedure in Example 4 Step 1 to generate theproduct in 75% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield.

EXAMPLE 634-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added pyridin-4-yl-methanesulfonyl chloridechloride according to the procedure in Example 4 Step 1 to generate theproduct in 75% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 77% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S−H] 676.20423 found 676.20405

EXAMPLE 644-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-chlorobenzyl bromide according to the procedure in Example 18 Step1-2.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in10% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 100% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S−H] 709.17000 found 709.16961

Example 654-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in43% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 88% yield. HRMS calc for[C₄₀H₃₆ClN₃O₆S−H] 720.19405 found 720.19398

EXAMPLE 664-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-chlorobenzyl bromide according to the procedure in Example 18 Step1-2.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in27% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 93% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S−H] 709.17000 found 709.16963

EXAMPLE 674-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2,5-dichlorobenzyl bromide according to the procedure in Example 18 Step1-2.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in59% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 100% yield. HRMS calc for[C₄₀H₃₅Cl₃N₂O₄S−H] 743.13103 found 743.13079

EXAMPLE 684-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-methoxybenzyl bromide according to the procedure in Example 18 Step1-2.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in20% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title compound in 100% yield. HRMS calc for[C₄₁H₃₉ClN₂O₅S−H] 705.21954 found 705.21909

EXAMPLE 694-{3-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoicacid

Step 1: The intermediate from Step 1 Example 56 was treated with SnCl₂according to the procedure in Step 1 Example 16 to yield the amino esterin 99% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₈ClN₃O₄S−H] 690.21988 found 690.21941

EXAMPLE 704-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2-Methylbenzyl bromide according to the procedure in Example 18 Step 1-2in quantitative yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride and theintermediate in Example 42 step 6 according to the procedure in Example42 Step 7 in 50% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 93% yield. HRMS calc for[C₄₁H₃₉ClN₂O₄S−H] 689.22463 found 689.22421

EXAMPLE 714-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-trifluoromethoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from4-trifluoromethoxybenzyl bromide according to the procedure in Example18 Step 1-2 in quantitative yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in48% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₆S−H] 761.17054 found 761.17031

EXAMPLE 724-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-fluoro-6-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from 2-Fluoro,6-nitrobenzyl bromide according to the procedure in Example 18 Step 1-2in quantitative yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in91% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 740.05

EXAMPLE 73 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Step 1: The c chloride intermediate was prepared from 3,5-dichlorobenzylbromide according to the procedure in Example 18 Step 1-2 in theoreticalyield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in100% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. m/z (M−1) 747.2. HRMScalc for [C₃₉H₃₃Cl₃N₂O₅S−H] 745.11030 found 745.10954.

EXAMPLE 744-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2,6-difluorobenzyl bromide according to the procedure in Example 18 Step1-2 in 95% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in86% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 71% yield. m/z (M−1) 714. HRMScalc for [C₃₉H₃₃ClF₂N₂O₅S−H] 713.16940 found 713.16906

EXAMPLE 754-(2-{1-benzhydryl-5-chloro-2-[2-({[(6-chloro-3-pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: (6-chloro-3-pyridinyl)-methanol (1.0 eq.) was taken up indichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.)and 1,3-bis(diphenylphosphino)propane (0.75 eq.) Ether was added to thesolution and filtration followed by concentration of the filtrateafforded (6-chloro-3-bromomethyl) pyridine in 62% yield.

Step 2: The sulfonyl chloride intermediate was prepared from the productof Step 1 according to the procedure in Example 18 steps 1-2.

Step 3: The methyl ester was prepared from the sulfonyl chloride andmethy4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in78% yield

Step 4: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₃₈H₃₃Cl₂N₃O₅S−H] 712.1445 found 712.14420.

EXAMPLE 764-(2-(1-benzhydryl-5-chloro-2-[2-({[(5,6-dichloropyridin-2-yl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: 5,6-dichloro-3-pyridinemethanol (1.0 eq.) was taken up indichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.)and 1,3-bis(diphenylphosphino)propane (0.75 eq.) Ether was added to thesolution and filtration followed by concentration of the filtrateafforded the 5,6-dichloro-3-bromomethylpyridine in 130% yield.

Step 2: The sulfonyl chloride intermediate was prepared from the productof Step 1 according to the procedure in Example 18 steps 1-2 in 81%yield

Step 3: The methyl ester was prepared from the sulfonyl chloride andmethy4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in79% yield

Step 4: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 109% yield. HRMS calc for[C₃₈H₃₂Cl₃N₃O₅S−H] 746.10554 found 746.10549.

EXAMPLE 774-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-methoxybenzyl bromide according to the procedure in Example 18 Step1-2 in 68% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in68% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 93% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+Na] 731.1953 found 731.1947.

EXAMPLE 784-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3,5-dimethylbenzyl bromide according to the procedure in Example 18 Step1-2 in 38% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in38% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 88% yield. m/z (M−1) 705.0 HRMScalc for [C₄₁H₃₉ClN₂O₅S−H] 705.21954 found 705.21916.

EXAMPLE 794-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2-methylbenzyl bromide according to the procedure in Example 18 Step 1-2in 35% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in35% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 90% yield. m/z (M−1) 691.0. HRMScalc for [C₄₀₁H₃₇ClN₂O₅S−H] 691.20389 found 691.20350

EXAMPLE 804-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2,6-dichlorobenzyl bromide according to the procedure in Example 18 Step1-2 in 3% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7 in 3%yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title diacid in 92% yield. m/z (M−1) 745.0

The intermediate amine, synthesized using method A, was treated withchloromethylsulfonyl chloride either under Schott and Baumman conditionsor under anhydrous conditions with an organic base yielded achloromethyl sulfonamide intermediate. This intermediate could betreated with a variety of nucleophiles in DMF with a suitable organicbase, Hunigs base, triethylamine etc, and heated until the reaction wascomplete. The resulting intermediates where then hydrolyzed to yield thefinal compound. The following examples were synthesized with method C:Examples 81-86 and 118-121.

EXAMPLE 814-(2-{1-benzhydryl-5-chloro-[2({[(phenylsulfanyl)-methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

The title compound was synthesized as depicted in Method C.

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added chloromethanesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 99%yield.

Step 2: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate(0.080M, 1.0 equiv.) and iPr₂NEt (3.4 equiv.) in N,N-dimethylformamidewas added thiophenol (2.1-2.5 equiv.) and the mixture was stirred at120° C. for 3.5 days. The reaction mixture was diluted with EtOAc andwashed with water and brine. The combined organic phase was dried overmagnesium sulfate and purified by flash chromatography.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. m/z (M−1) 709.11. HRMScalc for [C₃₉H₃₅ClN₂O₅S₂−H] 709.16031 found 709.15999.

EXAMPLE 82 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dimethyl-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1:To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2,6-dimethylthiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography with 25% EtOAc/hexane in 32% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 80% yield. m/z (M−1) 751.0. HRMScalc for [C₄₁H₃₉ClN₂O₅S₂−H] 737.19161 found 737.19128.

EXAMPLE 834-(2-{1-benzhydryl-5-chloro-2-[2-(2-methoxy-phenyl-sulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2-methoxythiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 30% EtOAc/hexane in 36% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 94% yield. m/z (M−1) 753.3. HRMScalc for [C₄₀H₃₇ClN₂O₆S₂−H] 739.17088 found 739.17052.

EXAMPLE 84 4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2-chloro-6-methylphenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]-benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2-chloro-6-methylthiophenol according tothe procedure in Example 81 step 2. The product was purified by theflash chromatography 25% EtOAc/hexane in 46% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. m/z (M−1) 771.2. HRMScalc for [C₄₀H₃₆Cl₂N₂O₅S₂−H] 757.13699 found 757.13730.

EXAMPLE 85 4-(2-{1-benzhydryl-5-chloro-2-[2-(3,5-dichloro-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 3,5-dichlorothiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 25% EtOAc/hexane in 40% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. m/z (M−1) 793.2. HRMScalc for [C₃₉H₃₃Cl₃N₂O₅S₂−H] 777.08237 found 777.08159.

EXAMPLE 864-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dimethoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)-sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 3,4-dimethoxythiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography with 35% EtOAc/hexane in 40% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid compound in 99% yield. m/z (M−1)783.3. HRMS calc for [C₄₁H₃₉ClN₂O₇S₂−H] 769.18144 found 769.18120.

The intermediate amine, synthesized using method A, was treated withchloroethanesulfonyl chloride under anhydrous conditions with an organicbase yielded a vinyl sulfonamide intermediate. This intermediate couldbe treated with a variety of nucleophiles in DMF with a suitable organicbase, Hunigs base, triethylamine etc, and heated until the reaction wascomplete. The resulting intermediates were then hydrolyzed to yield thefinal compound.

The following examples were synthesized with Method D: Examples 87-99and 100-105, 113-117, 122-125 and 139.

EXAMPLE 87 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin4-ylethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

The title compound was synthesis as depicted in Method D

Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(0.16M, 1.0 equiv.), Step 6, Example 1, and triethylamine (2.3 equiv.)in THF was added 2-chloroethanesulfonyl chloride (1.2 eq) dropwise.After 4 h the mixture was poured into brine and extracted with EtOAc.The combined organic phase was dried over magnesium sulfate and purifiedby column chromatography to afford 75% of the vinyl sulfonamide.

Step 2: To the product from step 1 in 1-propanol was added morpholine.After 5 h the reaction mixture was evaporated to dryness beforeredissolving in EtOAc. The organic phase was washed with brine, driedover magnesium sulfate, and purified by column chromatography to givethe desired methyl ester in 89% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. m/z (M−1) 702.17. HRMScalc for [C₃₈H₄₀ClN₃O₆S−H] 700.2535 found 700.22500.

EXAMPLE 884-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 1H-pyrazole according to the procedure in Example 87 step 2except that it was heated at 80° C. for 18 h, in 90% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 61% yield. m/z (M−1) 681.24. HRMScalc for [C₃₇H₃₅ClN₄O₅S−H] 681.19439 found 681.19407.

EXAMPLE 89 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-phenylamino-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and aniline according to the procedure in Example 87 step 2except that it was heated at 80° C. for 8 days, in 50% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. m/z (M−1) 706.26. HRMScalc for [C₄₀H₃₈ClN₃O₅S−H] 706.21479 found 706.21452.

EXAMPLE 904-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 1,4-dioxa-8-aza-spiro[4.5]decane according to the procedurein Example 87 step 2 except that it was stirred overnight, in 82% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 756.2. HRMScalc for [C₄₁H₄₄ClN₃O₇S−H] 756.25157 found 756.25142.

EXAMPLE 914-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-piperazinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 1-Pyridin-2-yl-piperazine according to the procedure inExample 87 step 2 except that it was stirred overnight, in 86% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 776.2. HRMScalc for [C₄₃H₄₄ClN₅O₅S−H] 776.26789 found 776.26750.

EXAMPLE 924-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 1H-[1,2,4]triazole according to the procedure in Example 87step 2 except that it was refluxed for 4 days, in 64% yield

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 682.1. HRMScalc for [C₃₆H₃₄ClN₅O₅S−H] 682.18964 found 682.18964.

EXAMPLE 934-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 3,5-dimethyl-1H-pyrazole according to the procedure inExample 87 step 2 except that it was refluxed for refluxed 24 hours, in95% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 62% yield. m/z (M−1) 709.2. HRMScalc for [C₃₉H₃₉ClN₄O₅S−H] 709.22569 found 709.22532.

EXAMPLE 944-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 3-methyl-1H-pyrazole according to the procedure in Example 87step 2 except that it was stirred overnight, in 88% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 86% yield. m/z (M−1) 695.2. HRMS calc for [C₃₈H₃₇ClN₄O₅S−H]695.21004 found 695.20951.

EXAMPLE 954-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 4-methyl-1H-pyrazole according to the procedure in Example 87step 2 except that it was refluxed for 2 days, in 81% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 93% yield. m/z (M−1) 695.2. HRMS calc for [C₃₈H₃₇ClN₄O₅S−H]695.21004 found 695.20954

EXAMPLE 964-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 2,6-dimethyl-piperidine according to the procedure in Example87 step 2 except that it was heated at 70° C. overnight, in 54% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 79% yield. m/z (M−1) 726.3. HRMS calc for [C₄₁H₄₆ClN₃O₅S−H]726.27739 found 726.27720.

EXAMPLE 974-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and imidazolidine-2-thione according to the procedure in Example87 step 2 except that it was refluxed for 3 days, in 17% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 88% yield. m/z (M−1) 715.3. HRMS calc for [C₃₇H₃₇ClN₄O₅S−H]715.18211 found 715.18161.

EXAMPLE 984-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and thiazolidine according to the procedure in Example 87 step 2except that it was refluxed overnight, in 33% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 93% yield. m/z (M−1) 702.3. HRMS calc for [C₃₇H₃₈ClN₃O₅S₂−H]702.18686 found 702.18659.

EXAMPLE 994-(2-{1-benzhydryl-5-chloro-2-[2-(2-[1,2,3]triazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 1H-[1,2,3]triazole according to the procedure in Example 87step 2 except that it was refluxed for 5 days, in 23% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 100% yield. m/z (M−1) 682.0. HRMS calc for [C₃₆H₃₄ClN₅O₅S−H]682.18964 found 682.18933.

EXAMPLE 100 4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate,Step 6, Example 42, (0.16M, 1.0 equiv.) and triethylamine (2.3 equiv.)in THF was added 2-chloroethanesulfonyl chloride (1.2 eq) dropwise.After 4 h the mixture was poured into brine and extracted with EtOAc.The combined organic phase was dried over magnesium sulfate and purifiedby column chromatography to afford the vinyl sulfonamide.

Step 2: To the product from step 1 in 1-propanol was added morpholine.After 5 h the reaction mixture was evaporated to dryness beforeredissolving in EtOAc. The organic phase was washed with brine, driedover magnesium sulfate, and purified by column chromatography to givethe desired methyl ester in 100% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. m/z (M−1) 698.12. HRMScalc for [C₃₉H₄₂ClN₃O₅S−H] 698.24609 found 698.24581.

EXAMPLE 1014-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(2,6-dimethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-propyl]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 100step 1 and 2,6-dimethylpiperdine according to the procedure in Example100 step 2 except that it was refluxed for heated at 80° C. for 1 d 17h, in 59% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. m/z (M−1) 724.20. HRMScalc for [C₄₂H₄₈ClN₃O₄S−H] 724.29813 found 724.29776.

EXAMPLE 1024-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-pyrazol-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-propyl]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 100step 1 and 3,5-dimethyl-1H-pyrazole according to the procedure inExample 100 step 2 except that it was refluxed for heated at 80° C. for1 d, in quantitative yield.

Step 2—The ester intermediate was hydrolyzed according to Step 8 Example1 to afford the title acid in 89% yield. m/z (M−1) 707.16. HRMS calc for[C₄₀H₄₁ClN₄O₄S−H] 707.24642 found 707.24597.

EXAMPLE 103 AND 1044-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid and4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The mixture of4-{2-[1-Benzhydryl-5-chloro-2-(2-ethenesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.2 M, 1.0 equiv.), 1H-tetrazole(4.0 equiv.) andiPr₂NEt(4.3 equiv.) in 1-propanol was refluxed overnight. It wasevaporated to dryness before redissolving in EtOAc. The organic phasewas washed with water and brine, dried over magnesium sulfate, purifiedby column chromatography to give two isomers in 41% and 52% yields,respectively.

Step 2: The ester intermediates were hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacids4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid in 92% yield. m/z (M−1) 683.3;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid in 83% yield. m/z (M−1) 683.3. HRMS calc for [C₃₅H₃₃ClN₆O₅S−H]683.18489 found 683.18458;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid in 83% yield. HRMS calc for [C₃₅H₃₃ClN₆O₅S−H] 683.18489 found683.18435.

The substituted nitro aromatic was treated with ethyl oxalate in thepresence of potassium or sodium in an alcoholic solvent. The resultingoxalate ester was treated with a suitable reducing agent, such as ironpowder, and the resulting amine cyclized to the indole under thereaction conditions. The carboxylate was next reduced with any of avariety of reducing agents, lithium aluminum hydride, dibal etc and theresulting alcohol was oxidized using reagents such as manganese dioxide,Swern condition NMO/TPAP etc. This 2 formyl indole was next alkylated bytreatment with a strong base such as Na/KHMDS, NaH, etc and thenalkylated with a suitable halide. The aldehyde was next treated withnitromethane and a base such as ammonium acetate to yield a vinyl nitrointermediate that could be reduced by a variety of agents such asLithium Aluminum Hydride or Zn(Hg) amalgam in HCl. The resulting aminewas sulfonylated using a sulfonyl chloride either under biphasicSchotten-Baumann conditions or anhydrous conditions with an organicbase. This intermediate could be reductively alkylated at C3 using analdehyde or an acetal under the action of a Bronsted or Lewis acid suchas trifluoroacetic acid and a reducing agent such as triethylsilane. Theresulting intermediate was hydrolyzed using a base, NaOH, KOH, LiOH anda mixture of solvents including an alcoholic solvent, water andtetrahydrofuran. The following Examples 105-107 were synthesized usingMethod E.

EXAMPLE 1054-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid

Step 1: To potassium (6.24 g) in ether at rt were added ethanol (40 mL,in 100 mL ether), diethyl oxalate (27.85 g, in 60 mL ether), and4-chloro-2-nitrotoluene (in 40 mL ether). The reaction mixture wasstirred at rt for 15 h and followed by sonication for 7 h before pouringonto cold 1N HCl. After neutralization, the aqueous layer was extractedwith EtOAc and the combined organic layers were washed with brine anddried. After evaporation, the crude3-(4-Chloro-2-nitro-phenyl)-2-oxo-propionic acid ethyl ester was useddirectly in the next step without further purification.

Step 2: To crude 3-(4-chloro-2-nitro-phenyl)-2-oxo-propionic acid ethylester (151 mmol) in ethanol:glacial HOAc (1:1, v/v, 560 mL) at rt wasadded iron powder (74.4 g) and the reaction mixture was stirred atreflux for 4 h. The mixture was filtered and evaporated to give aresidue which was redistributed in dichloromethane/1N HCl. The organiclayer was washed with 1N HCl, NaHCO₃, and brine and dried. Evaporationfollowed by crystallization (DCM) gave 6-Chloro-1H-indole-2-carboxylicacid ethyl ester as a pale yellow solid (16.8 g, 50% over 2 steps).

Step 3: To 6-chloro-1H-indole-2-carboxylic acid ethyl ester (8.57 g) inTHF at 0° C. was added lithium aluminum hydride solution (1M, in THF)dropwise and the reaction mixture was stirred for 3.5 h. The mixture wasquenched with H₂O, 15% NaOH, and H₂O before it was filtered and rinsedwith THF. Evaporation of the solvent gave 7.77 g of the crude(6-Chloro-1H-indol-2-yl)-methanol which was used directly in the nextstep.

Step 4: To (6-chloro-1H-indol-2-yl)-methanol (37.7 mmol) in THF at 0° C.was added manganese (IV) oxide and the mixture was stirred at rt for 16h. The mixture was filtered over celite and rinsed with THF and EtOAcand evaporated to near dryness. The solid was filtered and washed withcold EtOAc/hex to give 6-Chloro-1H-indole-2-carbaldehyde (62%, 2 steps).

Step 5: To 6-chloro-1H-indole-2-carbaldehyde (1 equiv.) in DMF at 0° C.was added NaH (1.25 equiv.) portionwise followed by benzhydryl bromide(1.46 equiv.) and Bu₄Nl (0.05 equiv.). The mixture was stirred at rt for42 h before quenching with cold 0.4N HCl at 0° C. After neutralization,the aqueous layer was extracted with ether and the organic layer waswashed with cold H₂O and dried. Flash chromatography on silica gel gave1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde in 40% yield.

Step 6: A solution of 1-benzhydryl-6-chloro-1H-indole-2-carbaldehyde(0.5M, 1 equiv.) and NH₄OAc (1 equiv.) in nitromethane was heated at 95°C. for 70 min. The mixture was diluted with EtOAc, washed with water,and dried. Evaporation of the volatiles, followed by trituration withether/hexane produced 1-Benzhydryl-6-chloro-2-(2-nitro-vinyl)-1H-indolein 48% yield.

Step 7: To lithium aluminum hydride (1M in THF, 4 equiv.) in THF at 0°C. was added 1-benzhydryl-6-chloro-2-(2-nitro-vinyl)-1H-indole (0.1M, 1equiv.) dropwise and the reaction mixture was stirred for 2 h. Themixture was quenched with H₂O, 15% NaOH, and H₂O, filtered throughcelite and rinsed with EtOAc. After evaporation, the residue waspurified by column chromatography to generate2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine in 40% yield.

Step 8: To 2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine was addedphenylmethanesulfonyl chloride according to the procedure in Example 1Step 7 to generateN-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamidein 90% yield.

Step 9: ToN-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-phenyl-methanesulfonamide(0.033M, 1 equiv.) in DCM at 0° C. were added 4-(2-oxo-ethoxy)-benzoicacid methyl ester (3.3 equiv.), triethylsilane (6 equiv.), and TFA (5equiv.). The reaction mixture was stirred at rt for 2 d 20 h beforeaqueous workup. Purification by silica gel chromatography followed byreverse phase HPLC gave4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester in 35% yield.

Step 10: The ester intermediate from step 9 was hydrolyzed according toStep 8 Example 1 to afford the title acid in 64% yield.

EXAMPLE 106 4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To 2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine, Example105 step 7 was added (3,4-dichloro-phenyl)-methanesulfonyl chlorideaccording to the procedure in Example 105 Step 7 to generateN-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamidein quantitative yield.

Step 2:N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamidewas reductively alkylated as described in Example 105 step 9 to give4-(2-{1-benzhydryl-6-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 38% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. m/z (M−1) 747.27.

EXAMPLE 107 4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,5-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To 2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethylamine, Example105 step 7 was added (3,5-dichloro-phenyl)-methanesulfonyl chlorideaccording to the procedure in Example 105 Step 7 to generateN-[2-(1-benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,5-dichloro-phenyl)-methanesulfonamidein quantitative yield.

Step 2:N-[2-(1-Benzhydryl-6-chloro-1H-indol-2-yl)-ethyl]-C-(3,4-dichloro-phenyl)-methanesulfonamidewas reductively alkylated as described in Example 105 step 9 to give4-(2-{1-benzhydryl-6-chloro-2-[2-(3,5-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 31% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+Na] 769.1 found 769.1079.

EXAMPLE 1084-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2-bromomethyl-benzonitrile according to the procedure in Example 18 Step1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 72% overall yield. HRMS calcd. forC₄₀H₃₅ClN₃O₅S (M+1): 704.1980; found: 704.1984. HRMS calcd. forC₄₀H₃₅ClN₃O₅S (M+1): 704.1980; found: 704.1984.

EXAMPLE 1094-{2-[1-Benzhydryl-5-chloro-2-(2-{[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2-bromomethyl-tetrahydro-pyran according to the procedure in Example 18Step 1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 20% overall yield HRMS calcd. forC₃₈H₃₈ClN₂O₆S (M−1): 685.2145; found: 685.2143.

EXAMPLE 1104-{2-[1-Benzhydryl-2-(2-{[(1,3-benzoxazol-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2-bromomethyl-benzooxazole according to the procedure in Example 18 Step1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 26% overall yield. HRMS calcd. forC₄₀H₃₅ClN₃O₆S (M+1): 720.1930; found: 720.1924.

EXAMPLE 1114-{2-[1-Benzhydryl-5-chloro-2-(2-{[(cyanomethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-bromomethyl-[1,2,4]oxadiazole according to the procedure in Example 18Step 1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 59% overall yield. HRMS calcd. forC₃₄H₃₁ClN₃O₅S (M+1): 628.1668; found: 628.1662.

EXAMPLE 1124-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-thienylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from3-bromomethyl 3-bromomethyl-thiophene according to the procedure inExample 18 Step 1-2 in 100% yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) according to the procedure in Example 1 Step 7.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 25% overall yield. HRMS calcd. forC₃₂H₃₁ClN₂O₅S₂ (M−1): 683.1447; found: 683.1445.

EXAMPLE 1134-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 2-methyl-pyrrolidine according to the procedure in Example 87step 2 in 91% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 99% yield. HRMS calc for [C₃₉H₄₂ClN₃O₅S−H] 698.24609 found698.24572.

EXAMPLE 1144-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 2-methyl-piperidine according to the procedure in Example 87step 2 in 91% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 96% yield. HRMS calc for [C₄₀H₄₄ClN₃O₅S−H] 712.26174 found712.26113.

EXAMPLE 1154-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2,5-dimethyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 2,5-dimethyl-pyrrolidine according to the procedure inExample 87 step 2 in 81% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 96% yield. HRMS calc for [C₄₀H₄₄ClN₃O₅S−H] 712.26174 found712.26114.

EXAMPLE 1164-(2-{1-Benzhydryl-5-chloro-2-[2-(2-thiomorpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and thiomorpholine according to the procedure in Example 87 step2 in 93% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 90% yield. HRMS calc for [C₃₈H₄₀ClN₃O₅S₂−H] 716.20251 found716.20217.

EXAMPLE 117 4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-piperidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and piperidine according to the procedure in Example 87 step 2 in99% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 92% yield. HRMS calc for [C₃₉H₄₂ClN₃O₅S−H] 698.24609 found698.24570.

EXAMPLE 118 4-{2-[1-benzhydryl-5-chloro-2-(2-o-tolylsulfanylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoic acid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added o-thiocresol according to the procedure inExample 81 step 2 and 3. The product was purified by the preparativeHPLC in 45% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. m/z (M−1) 723.07. HRMScalc for [C₄₀H₃₇ClN₂O₅S−H] 723.17596 found 723.17596.

EXAMPLE 119 4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2-chlorothiophenol according to theprocedure in Example 81 step 2. The product was purified by thepreparative HPLC in 53% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 100% yield. m/z (M−1) 743.08.HRMS calc for [C₃₉H₃₄Cl₂N₂O₅S₂−H] 743.12134 found 743.12111.

EXAMPLE 1204-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dichloro-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2,6-dichlorothiophenol according to theprocedure in Example 81 step 2. The product was purified by thepreparative HPLC in 15.7% yield and hydrolized acid in 37%.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 98% yield. m/z (M−1) 776.93. HRMScalc for [C₃₉H₃₃Cl₃N₂O₅S₂−H] 777.08237 found 777.08205.

EXAMPLE 1214-(2-{1-benzhydryl-5-chloro-2-[2-(2,5-dimethoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(chloromethyl)sulfonyl]amino}ethyl)-′1H-indol-3-yl]ethoxy}benzoate,Example 81 step 1, was added 2,5-dimethoxythiophenol according to theprocedure in Example 81 step 2. The product was purified by the flashchromatography 35% EtOAc/hexane in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 99.5% yield. m/z (M−1) 769.18HRMS calc for [C₄₁H₃₉ClN₂O₇S₂−H] 769.18144 found 769.18121.

EXAMPLE 1224-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3-hydroxy-pyrrolidine-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 3-pyrrolidinol according to the procedure in Example 87 step2 in 90% yield without the column purification.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 84% yield. m/z (M−1) 699.99. HRMS calc for [C₃₈H₄₀ClN₃O₆S−H]700.22535 found 700.22490.

EXAMPLE 1234-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(4-hydroxy-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and 4-hydroxypiperidine according to the procedure in Example 87step 2 in 95% yield without the column purification.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 42% yield. m/z (M−1) 714.03. HRMS calc for [C₃₉H₄₂ClN₃O₆S−H]714.24100 found 714.24085.

EXAMPLE 1244-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-dimethylaminomethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and N-(2-piperidylmethyl)-dimethylamine according to theprocedure in Example 87 step 2 in 90% yield without the columnpurification.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 71% yield. m/z (M−1) 754.94. HRMS calc for [C₄₂H₄₉ClN₄O₅S−H]755.30394 found 755.30344

EXAMPLE 1254-(2-{1-Benzhydryl-5-chloro-2-[2-(2-imidazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and imidazoleaccording to the procedure in Example 87 step 2except that it was heated at 120° C. for 4.5 days, in 87% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 60% yield. m/z (M−1) 681.17. HRMS calc for [C₃₇H₃₅ClN₄O₅S−H]681.19439 found 681.19409.

EXAMPLE 1264-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: The sulfonyl chloride intermediate was prepared from2,6-difluorobenzyl bromide according to the procedure in Example 18 Step1-2 in quantitative yield.

Step 2: The methyl ester was prepared from the sulfonyl chloride andmethyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) according to the procedure in Example 1 Step 7 in53% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. m/z (M−1) 711.2. HRMScalc for [C₄₀H₃₅ClF₂N₂O₄S−H] 711.19013 found 711.18965.

EXAMPLE 1274-{3-[1-benzhydryl-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: 2-methylindole was treated with the intermediate from Example 42step 1 and the procedure from Example 42 step 2 to yield the desiredproduct in 88%.

Step 2: The product from above was alkylated with benzhydryl bromideaccording to the proceure in Example 42 step 3 to yield the product in65%.

Step 3: The product from above was oxidized using the conditionsoutlined in Example 42 step 4 to yield the desired 2-formyl indole in85% yield.

Step 4: The indole from above was subjected to the nitro aldolconditions outlined in Example 42 step 6

Step 5: The vinyl nitro compound from above was reduced under theconditions outlined in Example 42 step 6 to yield the desired aminoindole in 39% yield.

Step 6: The amine from step 5 was treated with(3,4-dichlorophenyl)-methyl]sulfonyl chloride according to the procedurein Example 43 Step 7 which yielded 100% of the desired product.

Step 7: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 24% yield. HRMS calc for[C₄₀H₃₆ClN₂O₄S−H] 709.1700 found 709.16951.

EXAMPLE 1284-[3-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

Step 1: This compound was prepared from the intermediate in Example 127step 5 α-toluenesulfonyl chloride according to the procedure in Example43 Step 7 which yielded 83% of the desired product.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 42 to afford the title acid in 95% yield. HRMS calc for[C₄₀H₃₈N₂O₄S−H] 641.24795 found 641.24761.

The appropriately substituted halo amine is reacted with trifluoroaceticanhydride to yield an intermediate that could be treated with a Pd^(ii)catalyst in the presence of a base such as triethlyamine and Cul and asuitable alkyne under heat yielded the desired indole intermediate. Theprimary alcohol was protected as a silyl ether using a silyl chloridesuch as t-Butyldiphenyl silyl chloride and a base such as imidazole. Theprotected indole is then treated with oxallyl chloride followed bymethanol which produced the desired oxalate ester which could bealkylated using a suitable base such as cesium carbonate in refluxingacetonitrile and a halide. The oxallate could then be reduced via theaction of a suitable reducing agent such as borane. The resultingprimary alcohol was converted to a halide, using for example CBr₄ and aphosphine, which could then be a nucleophile such as a thiophenol. Theresulting thioether could be oxidized by a variety of oxidizing agentsincluding oxone and TPAP/NMO. The resulting sulfone can be deprotectedvia the action of a flouride source such as TBAF, CsF or HF. Theresulting alcohol could be converted to a halide or mesylate, forexample using methane sulfonyl chloride and an organic base, which couldthen be displaced by sodium azide in DMF.The resulting alkyl azide couldbe reduced under the action of triphenyl phosphine and wet THF. Theamine could be sulfonylated by the action of a sulfonyl chloride undereither biphasic Shcott and Baumman conditions, Aq. Bicarbonate anddichloromethane, or under anhydrous conditions consisting ofdichloromethane and an organic base such as Hunigs base. The reultingintermediate was hydrolyzed using a base, NaOH, KOH, LiOH and a mixtureof solvents including an alcoholic solvent, water and tetrahydrofuran.The following Examples 129-132 were synthesized using Method F.

EXAMPLE 1293-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

Step 1: 2-Bromo-4-chloroaniline(1.0 eq) was dissolved in CH₂Cl₂ (0.25M),then triethylamine and triflouroacetyl anhydride(1.1 eq each) wereadded. The resulting mixture was stirred at room temperature for 1 hour.Solvent was then stripped-off from the reaction mixture, and the residuewas purified by flash chromatography with dichloromethane as eluent togive the described product in 97% yield. m/z (M−H)⁻300.0.

Step 2: N-(2-Bromo-4-chlorophenyl)-2,2,2-trifluoroacetamide(step 1, 1.0eq) was mixed with 3-butyn-1-ol(2.0 eq),dichlorobis(triphenylphosphine)palladium(II) (2.5% eq),triethylamine(3.0 eq), Cul(5% eq) in DMF(0.2M) in a sealed vessel underN₂ and heated to 120° C. for 4 hours. The reaction mixture was thendiluted with ethyl acetate, washed with brine and dried over Na₂SO₄.Furthermore, evaporate the solvent and the residue was purified by flashcolumn chromatography with 2% MeOH/CH₂Cl₂ to give the describedproduct(A) in 67% yield. m/z (M−H)⁻ 194.09

Step 3: 2-(5-Chloro-1H-indol-2-yl)ethanol(step 2, 1.0 eq) andimidazole(2.0 eq) were dissolved in DMF(0.3M) at room temperature withstirring before tert-butylchlorodiphenylsilane (1.2 eq) was added. Theresulting mixture was kept stirred overnight at room temperature beforeit was quenched with a saturated sodium bicarbonate aqueous solution andextracted with ethyl acetate. Organic phase was washed with water andbrine and dried over Na₂SO₄. Solvent was removed and residue waspurified with column with CH₂Cl₂ as eluent to give the desired productas brown gum in over 90% yield. m/z (M−H)⁻ 433.0

Step 4:2-({[tert-Butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole(step 3, 1.0eq) was dissolved in ether (0.4M) and the solution was cooled to 0° C.Oxalyl chloride (1.2 eq) was added to the above cold solution withvigorous stirring. The reaction mixture was kept stirred at 0° C. for 1hour before EtOH was added, followed by NEt₃. The resulting mixture wasthen diluted with more EtOH before it was poured into water. Extractwith EtOAc. Organic phase washed with brine, dried over Na₂SO₄,concentrated to give the desired product as yellowish solid in 70%yield. m/z (M−H)⁻ 533.0

Step 5: Ethyl[2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate(step4, 1 eq), Ph₂CHBr(1.5 eq) and Cs₂CO₃(1.5 eq) were mixed in dryacetonitrile (0.1 M). The mixture was refluxed with stirring for 2hours. The reaction mixture was cooled to room temperature, added waterand extracted with EtOAc. Organic phase was concentrated and the residuewas columned with CH₂Cl₂ as eluent to give the desired product as orangegum in 45% yield. m/z (M+H)⁺ 701.3

Step 6: Ethyl[1-benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate(step5, 1 eq) was dissolved in THF (0.1M), then BH₃.Me₂S (2M in THF)(2 eq)wasadded to it. The resulting mixture was refluxed with stirring overnightunder N₂. The reaction mixture was cooled to room temperature, thenquenched slowly with 1N NaOH. Followed by EtOAc extraction, brine wash.Striping-off the solvent to give the described product in 65% yield. m/z(M+H)⁺ 645.0

Step 7:2-[1-Benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethanol(Step 6, leq) was dissolved in CH₂Cl₂(0.08M), then1,3-bis(diphenylphosphino)-propane (DPPP, 0.75 eq) was added. Thesolution was cooled to 0° C. under N₂, then CBr₄ (1.25 eq) was addedwith stirring. The stirring was continued for 2 hours while the reactiontemperature was allowed to return to room temperature. The solvent wasstripped off, and the residue was purified by passing through a shortcolumn with CH₂Cl₂ as eluent to give the desired product in quantitativeyield. m/z (M+H)⁺ 708.0

Step 8:1-Benzhydryl-3-(2-bromoethyl)-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole(Step7, 1 eq) was mixed with methyl-3-(4-mercaptolphenyl)propionate (1.5 eq)and K₂CO₃ (1.5 eq) in DMF(0.1M). The resulting mixture was stirred atroom temperature under N₂ for 2 hrs, then water was added, followedethyl acetate extraction, brine wash, and column purification (CH₂Cl₂ aseluent) to give 80% of the desired product as brownish gum. m/z (M+H)823.0

Step 9: Methyl3-[4-({2-[1-benzhydryl-2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate(Step 8, 1 eq) was dissolved in acetonitrile(0.1M), then molecular sieve(powder, 4 A,) and 4-methylmorphorline N-oxide(NMO)(4 eq) were addedunder N₂. After 5 min, n-Pr₄NRuO₄ (TPAP)(5% eq) was added to it. Theresulting mixture was heated to 40° C. with stirring and kept for 1.5hrs. Strip-off the solvent, residue was columned with CH₂Cl₂, then1%EtOAc/CH₂Cl₂ as eluent to give the desired product as white foam in44% yield. m/z (M+H)⁺ 855.1

Step 10: 3-[4-(2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanesulfonyl)-phenyl]-propionic acid methylester (Step 9, 1 eq) was dissolved in THF(0.1M) and cooled to 0° C.,followed by nBu₄NF (1M in THF) (1.2 eq). The resulting mixture wasstirred at 0° C. for 5′, then warmed up to room temperature and stirredfor 30′. Strip-off solvent. The residue was columned with EtOAc/CH₂Cl₂(1:9 to 1:4) as eluent to give the described intermediate as white foamin 90% yield. m/z (M+H)⁺ 616.20

Step 11: Methyl3-[4-{2-[1-benzhydryl-5-chloro-2-(hydroxyethyl)-1H-indol-3-yl]ethyl}-sulfonyl)phenyl]propanoate(step10, 1 eq) in dichloromethane(0.02M) was treated at 0° C. with MeSO₂Cl(2.0 eq) and Et₃N(2.5 eq) and stirred for 1 hour. The ice-bath wasremoved and the reaction mixture was stirred for another 1 hour at roomtemperature before it was diluted with CH₂Cl₂, washed with NaH₂PO₄,brineand dried over Na₂SO₄. Evaporate solvent to give the described productin quantitative yield. m/z (M+H)⁺ 695.0

Step 11: Methyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate(step11, 1.0 eq) was dissolved in DMF(0.03M) and treated with NaN₃ (3.0 eq).The resulting mixture was heated to 60° C. and stirred for 2 hours,then, was added water, extracted with ethyl acetate, washed with brineand dried with Na₂SO₄. Evaporation of solvent yields quantitatively thedescribed product. m/z (M+H)⁺ 641.1

Step 12: Methyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(step12, 1 eq) was dissolved in THF(0.1M), and treated withtriphenylphosphine(1.1 eq). The reaction mixture was kept stirred for 2days before the addition of water, then stirred overnight. Strip offsolvent, residue was columned with 4% MeOH:CH₂Cl₂ as eluent to give thedescribed product in 71% yield. m/z (M+H)⁺ 615.2

Step 13: Methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(step12, 1 eq) and (3,4-dichlorobenzyl)sulfonyl chloride(1.1) were dissolvedin CH₂Cl₂ (0.1M) at room temperature, then aqueous Na₂CO₃ solution wasadded with stirring. The stirring was continued for 2 hours. Then,organic phase was separated, washed with brine, dried with Na₂SO₄.Evaporate the solvent, the residue was columned with CH₂Cl₂ to 2%MeOH:CH₂Cl₂ as eluent to give 85% yield of the described product as whitesolid. m/z (M−H)⁻ 834.9

Step 14: Methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(step 13, 1.0 eq) was dissolved in THF:MeOH (1:1) (0.1M), then added 1NNaOH. The mixture was kept stirred overnight at room temperature. Thesolvent was stripped off and the residue was dissolved in water to forma basic solution, which was neutralized with diluted HCl solution toprecipitate the product. The solid was collected by filtration, washedwith water, rinsed with hexane, then dried to give the desired productin 86% yield. HRMS calc for [C₄₁H₃₇Cl₃N₂O₆S₂+H] 823.12314 found823.12292.

EXAMPLE 1303-(4-{[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoicacid

Step 1: The intermediate from example 129, step 12 was treated withα-toluenesulfonyl chloride according to the procedure in example 129step 13 to yield the desired compound in 94% yield.

Step 2: The intermediate from above was treated with NaOH according tothe procedure described in example 129, step 14 to yield the desiredacid in 92% HRMS calc for [C₄₁H₃₉ClN₂O₆S₂+H] 755.20109 found 755.20201.

EXAMPLE 1313-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

Step 1: The intermediate from example 129, step 12 was treated with(2,6-Difluoro-phenyl)-methanesulfonyl chloride according to theprocedure in example 129 step 13 to yield the desired compound in 42%yield.

Step 2: The intermediate from above was treated with NaOH according tothe procedure described in example 129, step 14 to yield the desiredacid in 83%. HRMS calc for [C₄₁H₃₇ClF₂N₂O₆S₂+H] 791.18224 found791.18257.

EXAMPLE 1323-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

Step 1: The intermediate from example 129, step 12 was treated with(2-fluoro-phenyl)-methanesulfonyl chloride according to the procedure inexample 129 step 13 to yield the desired compound in 42% yield.

Step 2: The intermediate from above was treated with NaOH according tothe procedure described in example 129, step 14 to yield the desiredacid in 86% yield. HRMS calc for [C₄₁H₃₈ClFN₂O₆S₂+H] 773.19166 found773.19213.

An intermediate from Method F could be alkylated at the C3 position withaldehydes or the corresponding acetals in the presence of a Lewis orBronsted acid, such as boron triflouride etherate or trifluoroaceticacid. The indole nitrogen may then be alkylated by treatment with astrong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodiumhydride or potassium hydride in a solvent such as DMF, DMSO or THFfollowed by exposure to the appropriate halide. The resulting thioethercould be oxidized by a variety of oxidizing agents including oxone andTPAP/NMO. The resulting sulfone can be deprotected via the action of aflouride source such as TBAF, CsF or HF. The resulting alcohol could beconverted to a halide or mesylate, for example using methane sulfonylchloride and an organic base, which could then be displaced by sodiumazide in DMF.The resulting alkyl azide could be reduced under the actionof triphenyl phosphine and wet THF. The amine could be sulfonylated bythe action of a sulfonyl chloride under either biphasic Shcott andBaumman conditions, Aq. Bicarbonate and dichloromethane, or underanhydrous conditions consisting of dichloromethane and an organic basesuch as Hunigs base. The reulting intermediate was hydrolyzed using abase, NaOH, KOH, LiOH and a mixture of solvents including an alcoholicsolvent, water and tetrahydrofuran. The following Examples 133, 135-138and 140-141 were synthesized by Method G.

EXAMPLE 1333-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid

Step 1: 3-[4-(2-Oxo-ethylsulfanyl)-phenyl ]-propionic acid ethyl ester(4.2 eq) was added to a solution containing2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 eq), TFA(3 eq), and 1,2-dichloroethane (0.1M) at 0° C. under N₂. Then Et₃SiH (12eq) was added and the reaction was allowed to return to room temperatureand stirred overnight. Quenched reaction with NaHCO_(3(aq)) andextracted with EtOAc and washed with brine and dried over sodiumsulfate. Purified with silica gel column and 1:5 EtOAc/Hexane as eluent.Obtained ethyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)propanoate(yellow oil) in 79% yield.

Step 2: Ethyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)propanoate(1 eq) was added to a suspension of NaH (1.1 eq) in DMF (0.38M) at 0° C.under N₂. After 30 minutes Ph₂CHBr was added and the reaction was warmedto room temperature. After 2.5 hours the reaction was quenched withNH₄Cl_((aq)) and extracted with EtOAc/Et₂O mix and washed with water andbrine and dried over sodium sulfate. Purified with silica gel column and1:6 EtOAc/Hexane. Obtained ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate(yellow gum) in 42% yield.

Step 3: NMO (4 eq) was added to a solution/suspension containing ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]propanoate(1 eq), ACN (0.1M), and molecular sieves (1 g/mmole of propanoate) underN₂. After 10 minutes TPAP (0.05 eq) was added and the mixture was heatedto 40° C. After 2 hours the reaction was cooled and filtered and thefiltrate was collected. Purified with silica gel column and 1:4EtOAc/Hexane. Obtained ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(white solid) in 86% yield.

Step 4: Tetrabutylammonium fluoride (1M in THF) (1.2 eq) was added to asolution of ethyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq) and THF (0.1M) at 0° C. under N₂. Warmed reaction to roomtemperature and after 30 minutes quenched with NH₄Cl_((aq)). Extractedwith EtOAc and washed with brine and dried over sodium sulfate. Purifiedwith silica gel column and 1:9 EtOAc/CH₂Cl₂. Obtained ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(white solid) in 88% yield.

Step 5: CH₃SO₂Cl (2 eq) and Et₃N (2.5 eq) were added to a solution ofethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq) in CH₂Cl₂ (0.02M) at 0° C. under N₂. After 1 hour the reactionwas warmed to room temperature. After an additional hour water was addedand extracted with CH₂Cl₂ and washed with brine and dried over sodiumsulfate. Removed solvent to obtain ethyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate(white solid) in 98% yield.

Step 6: Ethyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoate(1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together underN₂ and heated to 60° C. After 1 hour the reaction was cooled and waterwas added. Extracted with EtOAc/Et₂O mix and washed with water and brineand dried over sodium sulfate. Removed solvent to obtain ethyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(light-brown solid) in 96% yield.

Step 7: Ethyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq), PPh₃ (polymer supported) (1.3 eq), and THF (0.1M) were placedtogether under N₂. After 3 days water (1 mL/1 mmole propanoate) wasadded and reaction was stirred overnight. Filtered and collectedfiltrate. Purified with silica gel column and 2% MeOH in CH₂Cl₂.Obtained ethyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(light-brown solid) in 65% yield.

Step 8: (2-chlorobenzyl)sulfonyl chloride (2.2 eq) was added to amixture of ethyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂), and Na₂CO₃ (2.5 eq).After 2 hours more (2-chlorobenzyl)sulfonyl chloride (1.1 eq) was added.After an additional 1.5 hours the organic layer was recovered and washedwith brine and dried over sodium sulfate. Purified with silica gelpreparatory plate and 2% MeOH in CH₂Cl₂. Obtained ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(light-yellow gum) in 75% yield.

Step 9: Ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid (light-brown solid) in 83% yield. HRMS calc for [C₃₉H₃₆ClN₃O₄S+H]789.16211 found 789.16311.

The suitably substituted indole-2-carboxylate could be reduced via asuitable reducing agent such as lithium aluminum hydride, dibal etc andthen the resulting alcohol could be oxidized to the 2-formyl indoleusing MnO₂, under Swern oxidation conditions or other oxidants. Theindole nitrogen may then be alkylated by treatment with a strong basesuch as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride orpotassium hydride in a solvent such as DMF, DMSO or THF followed byexposure to the appropriate halide. The aldehyde was next treated withnitromethane and a base such as ammonium acetate to yield a vinyl nitrointermediate that could be reduced by a variety of agents such asLithium Aluminum Hydride or Zn(Hg) amalgam in HCl. The resulting aminewas sulfonylated using a sulfonyl chloride either under biphasic Schottand Baummen conditions or anhydrous conditions with an organic base.Treatment of the the resulting sulfonamide with a strong base such assodium bis(trimethylsilyl) amide, n-BuLi, sodium hydride or potassiumhydride in a solvent such as DMF, DMSO or THF followed by exposure to asilyl chloride such as t-butyldimethyl silyl chloride to generate theprotected sulfonamide. This material could be formylated at C3 usingstandard Vilsmeier conditions conditions of POCl₃/DMF. The thus formed3-formyl indole was reductively aminated using a suitable amine, areducing agent such as sodium triacetoxyborohydride and acid such asglacial acetic acid. The resulting intermediate was hydrolyzed using abase, NaOH, KOH, LiOH and a mixture of solvents including an alcoholicsolvent, water and tetrahydrofuran. Example 134 was synthesized byMethod H.

EXAMPLE 1344-({[(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)methyl]amino}methyl)benzoicacid

Step 1: 5-Chloro-1H-indole-2-carboxylic acid ethyl ester (1 eq.) wasdissolved in THF (0.4M), flushed with a nitrogen atmosphere and then themixture was cooled to 0° C. and LAH (3 eq of a 1M solution in THF) wasslowly added. The reaction was allowed to warm slowly to roomtemperature and stirred until TLC analysis indicated completion. Aftercooling the flask to 0° C., NaOH (60 ml 3N solution) was slowly addedand the reaction stirred until two layers were obtained. The layers wereseparated, aqueous was extracted 2× ethyl acetate, the combined organicswere washed with brine and then dried over magnesium sulfate andconcentrated to yield the desired alcohol that was used crude for thenext step.

Step 2: The product (1 eq.) from above was dissolved in THF (0.5 M) andtreated with manganese dioxide (3 eq), and stirred for 1.5 hours untilTLC analysis indicated that reaction was complete. The reaction wasfiltered through celite, dried over magnesium sulfate, and concentratedto yield the desired crude aldehyde in 82% yield.

Step 3: To the indole from above (1.0 eq) in DMF (0.36 M) at 25° C. wasadded NaH (1.2 eq, 60% dispersion in oil), and the brown solution wasstirred at 0 to −5° C. for 1 h and then bromodiphenylmethane was added(1.1 eq), and then the reaction mixture was stirred overnight. It wasthen quenched with water, diluted with ethyl acetate, washed with waterand brine, dried over sodium sulfate and purified by columnchromatography to yield 60% of the desired product.

Step 4: To the above aldehyde (1.0 equiv) in CH₃NO₂ (0.075 M) was addedammonium acetate (9 equiv) and the resulting mixture was heated toreflux overnight. The reaction mixture concentrated to a small volumeand then diluted with EtOAc and washed with brine. The aqueous phase wasextracted with EtOAc. The combined organic extracts were washed withbrine, dried over sodium sulfate and concentrated and purification bycolumn chromatography to the desired nitroolefin (51% yield).

Step 5: Zinc dust (20 equiv) was suspended in 5% aqueous HCl solution (8M Zn/5% HCl). To this mixture was added HgCl₂ (0.28 equiv). The mixturewas shaken for 10 min, the aqueous phase was decanted and replaced withfresh 5% HCl, and again the mixture was shaken for 5 min and the aqueousphase was removed. The zinc-mercury amalgam thus generated was thenadded to a mixture of the nitroolefin (1.0 equiv) and conc. HCl (80equiv) in THF (0.04 M nitroolefin/THF). The mixture was maintained at agentle reflux for 1 h. The formation of product was followed by TLCanalysis. The mixture was cooled to room temperature and the solids wereremoved by filtration through Celite. Conc. NH₄OH was added to thesolution phase and the mixture was concentrated on the rotaryevaporator. The residue was dissolved in CH₂Cl₂ and conc. NH₄OH. Theaqueous phase was extracted with CH₂Cl₂, and the organic phase waswashed with brine, dried over sodium sulfate, and concentrated to yieldthe desired crude amine(100%) that was used in the next step withoutpurification.

Step 7: To the amine form above (1.0 equiv) and sat. NaHCO₃ (0.14 M) inCH₂Cl₂ (0.07 M) was added α-toluenesulfonyl chloride (1.0 equiv). After1 h the mixture was poured into saturated sodium bicarbonate andextracted with CH₂Cl₂. The combined organic phase was washed with brine,dried over sodium sulfate and purified by column chromatography(gradient elution using 10% EtOAc-hexanes→20% EtOAc-hexanes) to afford40% of the desired sulfonamide.

Step 8: The sulfonamide from above was dissolved in DMF (0.5 M) undernitrogen atmosphere, cooled to 0° C., treated with sodium hydride (1.05eq of a 60 oil dipersion), stirred for 15 minutes to ensure aniongeneration, treated with t-butyldimethsilyl chloride (1.2 eq) and thenstirred for two hours at 0° C. at which time TLC analysis indicated thereaction was complete. The reaction was worked up by partitioningbetween ½ saturated ammonium chloride solution and ethyl acetate,extraction of the aqueous layers with ethyl acetate (2×), washingcombined organic layers with brine (1×), drying over magnesium sulfateand concentrating to yield quantitative crude yield of the desiredprotected sulfonamide.

Step 9: To DMF (˜1 ml) was added phosporous oxychloride (1.2 eq), thesereagents were stirred for 10 minutes and then a solution of the indole(1 eq) from above in DMF (0.8 M) was added. The resulting red reactionmixture is stirred for 4 hours, diluted with water and then the pH wasadjusted to 8 (total volume of aqueous added about ¾ of DMF addedinitially) and then the reaction was refluxed for 2 hours and finallycooled, extracted with dicloromethane, aqueous layer extracted withdichloromethane (2×), combined organic layers washed with brine (1×),dried over magnesium sulfate and concentrated to yield 75% of a crudealdehyde that was used without further purification.

Step 10: To the aldehyde from above (1 eq) in THF (1.2 M) was added4-aminomethyl-benzoic acid methyl ester (1.2 eq), sodiumtriacetoxyborohydride (1.5 eq) and acetic acid (glacial, 1.5 eq). Thereaction was stirred overnight and then worked up by the addition ofsaturated sodium bicarbonate and ethyl acetate, the layers wereseparated, the aqueous layer extracted with dichloromethane (2×),combined organic layers washed with brine (1×), dried over magnesiumsulfate and concentrated and purified via chromatography to yield 37% ofthe desired product.

Step 11: The resulting ester was hydrolyzed by stirring with 1N NaOH (5equiv) in THF (0.07 M) and enough MeOH to produce a clear solution. Thereaction was monitored by TLC (10% MeOH—CH₂Cl₂) for the disappearance ofstarting material. The mixture was stirred at room temperature for 72hours. The mixture was concentrated, diluted with H₂O, and acidified topH 5 using 1 M HCl. The aqueous phase was extracted with EtOAc and theorganic phase was washed with brine, dried over sodium sulfate, andconcentrated to afford the desired product in 83% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S−H] 676.20423 found 676.20397.

EXAMPLE 1354-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]-ethyl}-5-chloro-1H-indol-3yl)ethyl]sulfonyl}benzoicacid

Step 1: 2-(5-chloro-1H-indol-2-yl)ethanol (1 eq) was added to a solution(under N₂) containing tert-Butyldiphenylchlorosilane (1.2 eq), imidazole(2.5 eq), and DMF (1.8M). The reaction was stirred overnight. Quenchedwith NaHCO_(3(aq)) and extracted with a Et₂O/EtOAc mixture. The organiclayer was washed with water and brine and dried over sodium sulfate.Purified with silica gel column and 1:4 Hexane/CH₂Cl₂ as eluent.Obtained 2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole(yellow oil) in 98% yield.

Step 2: Methyl 4-[(2-oxoethyl)sulfanyl]benzoate (3.7 eq) was added to asolution containing2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indole (1 eq), TFA(3 eq), and 1,2-dichloroethane (0.1M) at 0° C. under N₂. Then Et₃SiH (12eq) was added and the reaction was allowed to return to room temperatureand stirred overnight. Quenched reaction with NaHCO_(3(aq)) andextracted with EtOAc and washed with brine and dried over sodiumsulfate. Purified with silica gel column and 1:5 EtOAc/Hexane as eluent.Obtained methyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate(yellow solid) in 79% yield.

Step 3: Methyl4-({2-[2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)benzoate(1 eq) was added to a suspension of NaH (1.1 eq) in DMF (0.37M) at 0° C.under N₂. After 30 minutes Ph₂CHBr (1.8 eq) was added and the reactionwas warmed to room temperature. After 3 hours the reaction was quenchedwith NH₄Cl_((aq)) and extracted with EtOAc/Et₂O mix and washed withwater and brine and dried over sodium sulfate. Purified with silica gelcolumn and 1:5 EtOAc/Hexane. Obtained methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]benzoate(yellow gum) in 65% yield.

Step 4: NMO (4 eq) was added to a solution/suspension containing methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfanyl)phenyl]benzoate(1 eq), ACN (0.1M), and molecular sieves (1 g/mmole of benzoate) underN₂. After 10 minutes TPAP (0.12 eq) was added and the mixture was heatedto 40° C. After 1.5 hours the reaction was cooled and filtered and thefiltrate was collected. Purified with silica gel column and 1:5EtOAc/Hexane. Obtained methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(white solid) in 71% yield.

Step 5: Tetrabutylammonium fluoride (1M in THF) (1.2 eq) was added to asolution of methyl3-[4-({2-[1-benzhydryl-2-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq) and THF (0.1M) at 0° C. under N₂. Warmed reaction to roomtemperature and after 1 hour quenched with NH₄Cl_((aq)). Extracted withEtOAc and washed with brine and dried over sodium sulfate. Purified withsilica gel column and 1:9 EtOAc/CH₂Cl₂. Obtained methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(white solid) in 86% yield.

Step 6: CH₃SO₂Cl (2 eq) and Et₃N (2.5 eq) were added to a solution ofmethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-hydroxyethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq) in CH₂Cl₂ (0.02M) at 0° C. under N₂. After 1 hour the reactionwas warmed to room temperature. After an additional hour water was addedand extracted with CH₂Cl₂ and washed with brine and dried over sodiumsulfate. Removed solvent to obtain methyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate(light-yellow solid) in 99% yield.

Step 7: Methyl3-(4-{[2-(1-benzhydryl-5-chloro-2-{2-[(methylsulfonyl)oxy]ethyl}-1H-indol-3-yl)ethyl]sulfonyl}phenyl)benzoate(1 eq), sodium azide (5 eq), and DMF (0.05M) were placed together underN₂ and heated to 60° C. After 1 hour the reaction was cooled and waterwas added. Extracted with EtOAc/Et₂O mix and washed with water and brineand dried over sodium sulfate. Removed solvent to obtain methyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(light-yellow solid) in 99% yield.

Step 8: Methyl3-[4-({2-[2-(2-azidoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq), PPh₃ (2 eq), and THF (0.1M) were placed together under N₂ andstirred overnight. Water (1 mL/1 mmole benzoate) was added and reactionwas again stirred overnight. The solution was concentrated and purifiedwith silica gel column and 3:1 EtOAc/Hexane followed by 5% MeOH inCH₂Cl₂. Obtained methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(light-yellow solid) in 99% yield.

Step 9: alpha-Toluene sulfonyl chloride (2 eq) was added to a mixture ofmethyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂), and Na₂CO₃ (2.5 eq).After 2 hours the organic layer was recovered and washed with brine anddried over sodium sulfate. Purified with silica gel preparatory plateand 3% MeOH in CH₂Cl₂. Obtained methyl4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate(off-white solid) in 94% yield.

Step 10: Methyl4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoate(1 eq), THF (0.1 M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}benzoicacid (off-white solid) in 92% yield. HRMS calc for [C₃₉H₃₅ClN₂O₆S₂−H]725.15523 found 725.15437.

EXAMPLE 1364-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

Step 1: (2-chlorobenzyl)sulfonyl chloride (3.4 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours more (2-chlorobenzyl)sulfonylchloride (3.4 eq) was added. After an additional 1.5 hours the organiclayer was recovered and washed with brine and dried over sodium sulfate.Purified with silica gel preparatory plate and 3% MeOH in CH₂Cl₂.Obtained methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(orange gum) in 40% yield.

Step 2: Methyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (red-orange solid) in 80% yield. HRMS calc for [C₃₉H₃₄Cl₂N₂O₆S₂+H]761.13081 found 761.13146.

EXAMPLE 1374-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

Step 1: (2,6-difluorobenzyl)sulfonyl chloride (3.4 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(off-white solid) in 87% yield.

Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (white-yellow solid) in 96% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂O₆S₂−H] 761.13638 found 761.13565.

EXAMPLE 1384-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

Step 1: (2-fluorobenzyl)sulfonyl chloride (3.4 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(off-white solid) in 82% yield.

Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (off-white solid) in 99% yield. HRMS calc for [C₃₉H₃₄ClFN₂O₆S₂−H]743.1458 found 743.14511.

EXAMPLE 1394-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87step 1 and pyrrolidine according to the procedure in Example 87 step 2in 92% yield without the column purification.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 92% yield. HRMS calc for [C₃₈H₄₀ClN₃O₅S−H] 684.23044 found684.23009.

EXAMPLE 140 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoic acid

Step 1: (3,4-dichlorobenzyl)sulfonyl chloride (2.1 eq) was added to amixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 1 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(white solid) in 87% yield.

Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (white-yellow solid) in 93% yield. HRMS calc for[C₃₈H₃₃Cl₃N₂O₆S₂−H] 793.07728 found 793.07629

EXAMPLE 1414-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

Step 1: (2,6-dimethylbenzyl)sulfonyl chloride (3.0 eq, example 52,step 1) was added to a mixture of methyl3-[4-({2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethyl}sulfonyl)phenyl]benzoate(Example 135, Step 8, 1 eq), CH₂Cl₂ (0.08M), water (1 mL/1 mL CH₂Cl₂),and Na₂CO₃ (2.5 eq). After 2 hours the organic layer was recovered andwashed with brine and dried over sodium sulfate. Purified with silicagel preparatory plate and 3% MeOH in CH₂Cl₂. Obtained methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(light-brown solid) in 81% yield.

Step 2: Methyl4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate(1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) werestirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland collected resulting precipitate by filtration. Obtained4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid (white solid) in 99% yield. HRMS calc for [C₄₁H₃₉ClN₂O₆S₂+H]753.18653 found 753.18597.

Method J provides an alternative reaction scheme to a subset of thecompounds contained in this document. A suitably substituted aniline ishalogenated using ICl, I₂, or Br₂ and then the amine is protected as acarbamate, using for example triethylamine and a chloroformate. Thisaryl halide is coupled to a suitably functionalized alkyne under thereaction of Pd and copper catalysis in the presence of a base such astriethylamine. This resulting product could be cyclized using Pdcatalysis in the presence of allyl chloride and a substituted oxirane.The indole nitrogen may then be alkylated by treatment with a strongbase such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride orpotassium hydride in a solvent such as DMF, DMSO or THF followed byexposure to the appropriate halide. The allyl indole could then betreated with 9-BBN and then a palladium catalyst followed by an aryl orvinyl iodide to effect a Suzuki coupling reaction. The resultingintermediate could be deprotected using a hydrazine or an alkyl amine toyield the primary amine. This amine could then be treated with therequisite sulfonyl chloride under biphasic conditions, aqueous sodiumbicarbonate/dichloromethane, or in organic solvent with the addition ofa hindered organic amine base. The final hydrolysis was accomplishedunder basic conditions with sodium hydroxide in water and methanol andTHF at room temperature or at elevated temperature. Alternatively it maybe cleaved by treatment with sodium thiomethoxide in a solvent such asTHF or DMF at elevated temperatures (50° C.-100° C.).

Method K provides an alternative method to prepare compounds of thisinvention. A suitably substituted aniline is halogenated using ICl, I₂,or Br₂ and then the amine is protected as a carbamate or amide,using forexample trifluoroacetic anhydride triethyamine and dimethylaminopyridine. This intermediate is then reacted with a suitablyfunctionalized alkyne under palladium and copper catalysis in thepresence of a base. The resulting aryl alkyne is cyclized to the indoleby heating with an amine such as piperidine. Standard Mitsunobu reactionconditions, a phosphine, an azodicarboxylate and phthalamide are used togenerate the protected amine. The indole may be alkylated at the C3position (the indole 3-position carbon atom) with aldehydes or thecorresponding acetals in the presence of a Lewis or Bronsted acid, suchas boron triflouride etherate or trifluoroacetic acid. The indolenitrogen may then be alkylated by treatment with a strong base such assodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassiumhydride in a solvent such as DMF, DMSO or THF followed by exposure tothe appropriate halide. The resulting intermediate could be deprotectedusing a hydrazine or an alkyl amine to yield the primary amine. Thisamine could then be treated with the requisite sulfonyl chloride underbiphasic conditions, aqueous sodium bicarbonate/dichloromethane, or inorganic solvent with the addition of a hindered organic amine base. Thefinal hydrolysis was accomplished under basic conditions with sodiumhydroxide in water and methanol and THF at room temperature or atelevated temperature. Alternatively it may be cleaved by treatment withsodium thiomethoxide in a solvent such as THF or DMF at elevatedtemperatures (50° C.-100° C.).

Method L provides another alternative method to prepare compounds ofthis invention. A suitably substituted halo aniline, see methods J andK, and a symmetric alkynol or a monoprotected alkynol, for example THPprotection, are reacted in the presence of a base, copper and palladiumcatalysis, followed by deprotection under acidic conditions if amonoprotected substrate is used yielded the symmetrical indole diol. Thediol is desymmetrized by treatment with carbonyl diimidazole in asuitable solvent and then the primary alcohol was substituted understandard Mitsunobu conditions, a phosphine, an azodicarboxylate and analcohol were used to generated the desired ether. The carbamate could beopened up by reaction with sodium azide to yield the alkyl azide. Theindole nitrogen may then be alkylated by treatment with a strong basesuch as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride orpotassium hydride in a solvent such as DMF, DMSO or THF followed byexposure to the appropriate halide. Treatment with triphenyl phosphinein wet THf delivered the desired alkyl amine. This amine could then betreated with the requisite sulfonyl chloride under biphasic conditions,aqueous sodium bicarbonate/dichloromethane, or in organic solvent withthe addition of a hindered organic amine base. The final hydrolysis wasaccomplished under basic conditions with sodium hydroxide in water andmethanol and THF at room temperature or at elevated temperature.Alternatively it may be cleaved by treatment with sodium thiomethoxidein a solvent such as THF or DMF at elevated temperatures (50° C.-100°C.).

Method M provides a further strategy to furnish compounds of thisinvention. A suitably substituted aniline is halogenated using ICl, I₂,or Br₂ and then the amine can be alkylated using an organic base and ahalide. The thus formed alkyl amine is then reacted under palladiumcatalyzed conditions in the presence of a chloride source a base andwith or without a phsophine and the requisite alkyne to yield theindole. When the Z in the alkyne is NHSO₂(CH₂)_(n2)X1R1 the synthesis isfinished by hydrolysis under basic conditions with sodium hydroxide inwater and methanol and THF at room temperature or at elevatedtemperature. Alternatively it may be cleaved by treatment with sodiumthiomethoxide in a solvent such as THF or DMF at elevated temperatures(50° C.-100° C.).

When Z=NH₂

The resulting indole can then be treated with the requisite sulfonylchloride under biphasic conditions, aqueous sodiumbicarbonate/dichloromethane, or in organic solvent with the addition ofa hindered organic amine base. The final hydrolysis was accomplishedunder basic conditions with sodium hydroxide in water and methanol andTHF at room temperature or at elevated temperature. Alternatively it maybe cleaved by treatment with sodium thiomethoxide in a solvent such asTHF or DMF at elevated temperatures (50° C.-100° C.).

When Z=OH

The resulting alcohol could be converted to a halide or mesylate, forexample using methane sulfonyl chloride and an organic base, which couldthen be displaced by sodium azide in DMF. The resulting alkyl azidecould be reduced under the action of triphenyl phosphine and wet THF.The amine could be sulfonylated by the action of a sulfonyl chlorideunder either biphasic Shcott and Baumman conditions, Aq. Bicarbonate anddichloromethane, or under anhydrous conditions consisting ofdichloromethane and an organic base such as Hunigs base. The resultingintermediate was hydrolyzed using a base, NaOH, KOH, LiOH and a mixtureof solvents including an alcoholic solvent, water and tetrahydrofuran.

Method N provides a further strategy to furnish a subset of thecompounds of this invention. The C3 functionalized-2-formyl indole (Seemethod A) was reacted under Wittig, or other organometallic conditions,to generate an alkeneoate ester. This ester could be converted to theacid by treatment with Pd and the resulting unsaturated acid was reducedvia hydrogenation. The alkyl acid was activated by conversion to theacid chloride, under the action of oxalyl chloride, or the acidflouride, via cyanuric flouride, and then treated with a suitableborohydride reducing agent to generate the alcohol. The alcohol wasconverted to the bromide using triphenyl phosphine andcarbontetrabromide and then displaced by the anion of the sulfonamide,generated by treating the primary sulfonamide with a strong base, suchas NaH, n-BuLi etc, to yield the desired secondary sulfonamide. Theresulting ester intermediate was hydrolyzed using a base, NaOH, KOH,LiOH and a mixture of solvents including an alcoholic solvent, water andtetrahydrofuran.

EXAMPLE 1424-[2-(1-benzhydryl-2-{3-[(benzylsulfonyl)amino]propyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: 5.0 g of4-[2-(1-Benzhydryl-2-formyl-1H-indol-3-yl)-ethoxy]-benzoic acid methylester, Step 4, Example 1, (0.0092M, 1.0 eq.) and 5.0 g ofallyl(triphenylphosphoranylidene) acetate (0.0139M, 1.5 eq.) weredissolved in 250 mL of tetrahydrofuran at room temperature. The paleyellow solution was stirred for one hour. TLC indicated a new spot at□Rf of +0.5 in 1:1 hexanes/ethyl acetate and no remaining startingindole. The reaction was poured into 500 mL of ethyl acetate and washedwith water (2×125 mL) and brine (2×125 mL). The organic layer was driedover magnesium sulfate and filtered. The filtrate was evaporated to ayellow oil which was dissolved in 50 ml 1:1 hexanes/ethyl acetate andfiltered through a plug of silica gel to remove baseline material. Thisleft 5.23 g of4-{2-[2-(2-Allyloxycarbonyl-vinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a yellow oil (91% yield).

Step 2: 6.12 g of4-{2-[2-(2-Allyloxycarbonyl-vinyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.098M, 1 eq.) and 1.12 g oftetrakis(triphenylphosphine) palladium (0) (0.001M, 0.1 eq.) were addedto 75 mL of THF. To the reaction 8.60 ml of morpholine (0.098M, 1 eq.)was added drop-wise over 20 min. After addition was complete thereaction was stirred at room temperature for 4 hours. The reaction waspoured into 250 mL of ethyl acetate and the organic solution wasextracted with 1N NaOH (2×75 mL). The aqueous layers were combined andacidified with 1N HCl, the acidic solution was extracted with ethylacetate (3×75 mL). The organic layers were combined and washed withbrine (1×50 mL), dried over magnesium sulfate, filtered and evaporatedto yield4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a yellow oil (5.40 g, 97% yield).

Step 3: 400 mg of4-{2-[1-Benzhydryl-2-(2-carboxy-vinyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0007M, 1 eq.) was dissolved in 15 mL of methanol.To the solution, 80 mg of 5% platinum on activated carbon was added as aslurry in 5 mL of methanol. The black suspension was placed under ahydrogen atmosphere via a balloon and stirred for 24 hrs. at roomtemperature. The hydrogen was evacuated and another 80 mg of 5% platinumon activated carbon in 5 mL of methanol was added and the reaction wasagain placed under a hydrogen atmosphere via a balloon and stirred foranother 24 hrs. at room temperature. The reaction was monitored via NMRand at this point complete conversion was indicated. The reaction wasfiltered through Celite and the filtrate was evaporated to give4-{2-[1-Benzhydryl-2-(2-carboxy-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a yellow-green solid (320 mg, 79% yield).

Step 4: 100 mg of4-{2-[1-Benzhydryl-2-(2-carboxy-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0002M, 1 eq.) was dissolved in 1.0 ml of anhydrousmethylene chloride. To the solution 33.5 mg of oxalyl chloride (0.0003M,1.5 eq.) was added and the reaction stirred for one hour at roomtemperature. The reaction was then evaporated to dryness and the residuedissolved in 1.0 mL of anhydrous ethyl ether to which 0.027 mL of TMEDAwas added. To this solution 0.35 mL of zinc borohydride solution inether prepared by the literature method (Tet. Lett. Vol. 22, pg. 4723,1981) was added. The reaction was stirred for 15 min. at roomtemperature and quenched with 1.0 mL of water. The reaction was dilutedwith 10 mL of ethyl ether and the water layer separated, the organiclayer was dried over magnesium sulfate, filtered and evaporated to aclear oil. The oil was chromatographed with ethyl acetate/hexanes (1:9)to result in isolation of4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester as a white foam (81 mg, 83% yield).

Step 5: 104.0 mg of4-{2-[1-Benzhydryl-5-chloro-2-(3-hydroxy-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0002M, 1.0 eq.) was dissolved in 2.0 mL ofanhydrous methylene chloride. To the solution 116.0 mg of polystyrenebound triphenylphosphine was added (1.61 mmol/g, 0.0002M, 1.0 eq.)followed by 125.0 mg of carbon tetrabromide (0.0004M, 2 eq.). Thesuspension was stirred for 2 hrs at room temperature at which point thereaction was filtered and the filtrate evaporated to an orange oil. Theoil was purified via column chromatography with ethyl acetate/hexanes(2:98) to give 100 mg (86%) of4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester title as a yellow foam.

Step 6: 33.3 mg of α-toluenesulfonamide (0.0002M, 1.2 eq.) was dissolvedin 0.5 mL of DMF and added to a slurry of 8.0 mg of 60% sodium hydride(0.0002M, 1.2 eq.) in 0.5 mL of DMF. The reaction was stirred for 30min. at which point 100 mg of4-{2-[1-Benzhydryl-2-(3-bromo-propyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (0.0002M, 1.0 eq.) in 0.5 mL of DMF was added and thesolution was stirred for an additional 1 hour. The reaction was quenchedwith water and diluted with 10 mL of ethyl acetate. The organic layerwas washed with water(2×5 mL) and brine (2×5 mL), dried over magnesiumsulfate and evaporated to a yellow oil. The residue was purified viacolumn chromatography (ethyl acetate/hexanes 5:95) to give 20 mg (17%)of4-{2-[1-Benzhydryl-5-chloro-2-(3-phenylmethanesulfonylamino-propyl)-1H-indol-3-yl]-ethoxy}-benzoicacidmethyl ester as a clear oil.

Step 7: 20.0 mg of indole from Example 6 (0.00002M, 1 eq.) washydrolyzed as in Example 1 Step 8 to yield the title compound (13.0 mg,88% yield) m/z (M−1) 691.

The appropriately substituted halo amine is reacted with a suitablehalide and a tertiary amine base to yield an N-alkylated substrate for aShonigishiru coupling (with an alkynol in the presence of Pd^(ii) and asuitable base). This arylalkynol is cyclized to the indole under theaction of a copper halide and heat. The free alcohol was protected witha silyl protecting group by reaction with a silyl chloride in thepresence of a base such as imidazole. This indole was next C₃ acylatedby reaction with a suitable acid chloride and the resulting compoundreduced with most reducing agents but preferably borane or a boranecomplex. The primary alcohol was then oxidized to an aldehyde by anynumber of oxiidizing agents, including oxalyl chloride/DMSO (swernconditions) or TPAP/NMO. This aldehyde was subjected to reductiveamination conditions, which include a borohydride reducing agent and insome cases a protice acid, and a primary or secondary amine. The silylether was then deprotected with a flouride source including CsF, TBAF,HF etc. This free alcohol was converted into a leaving group, halidewith CBr₄ and a phosphine, or a sulfonate ester with methane sulfonylchloride and a tertiary amine. The activated alcohol is reacted withsodium azide in either DMF or DMSO to yield the desired azide which inturn was reduced under Staudinger conditions, phosphine and THF/H₂O, orvia hydrogenation using hydrogen and a suitable catalyst. The aminecould be sulfonylated by the action of a sulfonyl chloride under eitherbiphasic Shcott and Baumman conditions, Aq. Bicarbonate anddichloromethane, or under anhydrous conditions consisting ofdichloromethane and an organic base such as Hunigs base. The resultingintermediate was hydrolyzed using a base, NaOH, KOH, LiOH and a mixtureof solvents including an alcoholic solvent, water and tetrahydrofuran.

The following Examples 143-151 were synthesized with Method N.

EXAMPLE 1434-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]amino}benzoicacid

Step 1: To a solution of 4-chloro-2-iodoaniline (16.5 g, 65.1 mmol) inDMF (250 mL) at rt were added α-bromodiphenylmethane (21.5 g, 84.6 mmol)and ^(i)Pr₂NEt (23 mL, 130 mmol) and the reaction mixture was heated at45° C. overnight. After the volatile was removed under reduced pressure,the residue was dissolved in EtOAc, washed with water (3×) and brine anddried over MgSO₄. Purification on SiO₂ column chromoatography (hexanesto 5% EtOAc/hexanes) gave the desiredBenzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g, 97% yield) as ayellowish solid.

Step 2: A mixture of benzhydryl-(4-chloro-2-iodo-phenyl)-amine (26.1 g,62.2 mmol), PdCl₂(PPh₃)₂ (1.90 g, 2.67 mmol), Cul (1.2 g, 6.2 mmol),3-butyn-1-ol, and Et₃N (120 mL) was stirred at 45° C. for 20 hours. Thereaction mixture was filtered through celite and rinsed with EtOAc. Thefiltrate was concentrated, redissolved in EtOAc, washed with water (3×)and brine, and dried over MgSO₄. The crude4-[2-(Benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) was usedin the next step directly without further purification.

Step 3: A solution of the crude4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) and Cul(2.7 g, 14.1 mmol) in DMF (200 mL) was heated at 125° C. for 24 hours.The reaction mixture was filtered through celite and rinsed with EtOAc.The filtrate was concentrated, redissolved in EtOAc, washed with water(3×) and brine, and dried over MgSO₄. Silica gel column chromatography(30% EtOAc/hexanes) yielded the desired2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethanol as a yellow solid (14.5g, 73% over 2 steps).

Step 4: To a solution of 2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethanol(15.3 g, 42.3 mmol) in CH₂Cl₂ (190 mL) at 0° C. were added imidazole(3.72 g, 55.0 mmol) and TBDPSCl (13.2 mL, 50.8 mmol). After stirring atthe same temperature for 1.5 hours, the reaction mixture was washed withcold water (3×) and brine, and dried over MgSO₄. The crude silyl etherwas used in the next step directly without further purification.

Step 5: To a solution of the crude silyl ether in Et₂O (200 mL) at 0° C.was added oxalyl chloride (4.84 mL, 55.5 mmol) dropwise. The reactionmixture was allowed to warm to rt and stirring continued for 4 hoursbefore Et₃N (35 mL) and MeOH (10 mL) were added. The mixture was washedwith water, brine, and dried over MgSO₄. The crude keto ester was useddirectly in the next step.

Step 6: To the keto ester in THF (300 mL) was added BH₃.Me₂S (10 M, 36mL) dropwise at rt and the reaction mixture was refluxed overnight. Themixture was cooled at 0° C. before NaOH (30%, 150 mL) was added andstirring continued for 30 min. THF was removed under reduced pressureand the reaction mixture was extracted with EtOAc, washed with water,brine, and dried over MgSO₄. Purification on column chromatography (15to 20% EtOAc/hexanes) yielded the desired product as a white solid (15.9g, 24.7 mmol, 58% over 3 steps).

Step 7: To a solution of oxalyl chloride (0.372 mL, 4.27 mmol) in CH₂Cl₂(10 mL) at −78° C. was added DMSO (0.661 mL, 9.31 mmol) dropwise. Thereaction mixture was stirred at the same temperature for 5 min before asolution of2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(2.50 g, 3.88 mmol) in CH₂Cl₂ (8 mL) was introduced. After additional 40min stirring, ^(i)Pr₂NEt (3.38 mL, 19.4 mmol) was added and the reactionwas quenched with cold water (5 mL) and extracted with CH₂Cl₂. Theorganic layer was dried over MgSO₄ and evaporated. The crude{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehydewas used directly in the next step.

Step 8: To a solution of the crude aldehyde (3.88 mmol) in1,2-dichloroethane (39 mL) at 0° C. were added methyl 4-aminobenzoate(645 mg, 4.27 mmol), acetic acid (1.33 mL), and NaBH(OAc)₃. The reactionmixture was allowed to warm to rt overnight and quenched with coldNaHCO₃. An extractive workup furnished the desired4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoicacid methyl ester which was used directly in the next step withoutfurther purification.

Step 9: To4-(2-{1-benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethylamino)-benzoicacid methyl ester (3.88 mmol) in THF (25 mL) at 0° C. was added amixture of HOAc:1M TBAF (in THF) (2.3 mL:5.8 mL) and the reactionmixture was allowed to stir at rt for 18 h. Extractive workup followedby trituration with 5% EtOAc/hex gave the desired4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester with slight impurity as an off-white solid (92%, over3 steps).

Step 10: To a solution of4-{2-[1-benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (1.64 g, 3.04 mmol) in CH₂Cl₂ at 0° C. were added Et₃N(0.636 mL, 4.56 mmol) and MsCl (0.282 mL, 3.64 mmol). After stirring atthe same temperature for 35 min, the reaction mixture was quenched withcold water. An extractive workup revealed the crude mesylate as anoff-white solid (1.70 g, 90%).

Step 11: A solution of the crude mesylate (1.70 g, 2.75 mmol) and NaN₃(89 mg, 13.8 mmol) in DMF (14 mL) was stirred at 80° C. for 6 h. Thereaction mixture was diluted with EtOAc and subjected to an aqueousworkup followed by flash column chromatography to yield the desired4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (813 mg, 52% yield).

Step 12: To4-{2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (400 mg, 0.709 mmol) in THF (4 mL) at 0 C. was addedPh₃P (223 mg, 0.851 mmol) in portions. The reaction mixture was stirredat rt for 11 h and 35° C. for 4 h before water (50 uL) was added andstirring continued overnight. The reaction mixture was diluted withEtOAc, dried with MgSO₄ and purified by flash column chromatography(EtOAc to 20%MeOH/EtOAc with 1% Et₃N) to give the desired4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoicacid methyl ester (201 mg, 53%) as a solid.

Step 13: The intermediate from step 12 was treated withα-toluenesulfonyl chloride according to the procedure in Example 87 step2 to generate the desired product in 72% yield.

Step 14: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 87% yield. HRMS calc for[C₃₉H₃₆ClN₃O₄S+H] 678.21879 found 678.2178.

EXAMPLE 1444-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid

Step 1: The intermediate from example 143 step 12 was treated with2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure inExample 87 step 2 to generate the desired product in 85% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 96% yield. HRMS calc for[C₃₉H₃₅Cl₂N₃O₄S+H] 712.17981 found 712.17895.

EXAMPLE 1454-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid

Step 1: The intermediate from example 143 step 12 was treated with2-methoxy-benzenesulfonyl chloride according to the procedure in Example87 step 2 to generate the desired product in 85% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 92% yield. HRMS calc for[C₃₉H₃₆ClN₃O₅S+H] 694.2137 found 694.21311.

EXAMPLE 1464-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid

Step 1: The intermediate from example 143 step 12 was treated with2-chloro-benzenesulfonyl chloride according to the procedure in Example87 step 2 to generate the desired product in 21% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 94% yield. HRMS calc for[C₃₈H₃₃Cl₂N₃O₄S+H] 698.16416 found 698.16365.

EXAMPLE 1474-[[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl](methyl)amino]benzoicacid

Step 1: Crude{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehydefrom step 7, example 142 was treated with 4-Methylamino-benzoic acidmethyl ester according to the procedure in Example 142 step 8 to yieldthe desired4-[(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethyl)-methyl-amino]-benzoicacid methyl ester in 73% yield.

Step 2: The title compound was prepared according to the proceduredescribed for Example 142 step 9. The crude4-({2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester was used in the next step directly without furtherpurification.

Step 3-6:4-({2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester was prepared according to the procedure described forexample 142 steps 10-12 in 61% (3 steps).

Step 7: A solution of4-({2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester (410 mg, 0.709 mmol) and 10% Pd/C (155 mg) inMeOH:CH₂Cl₂ (=7 mL:1 mL) was stirred under H₂ atmosphere (1 atm) for 2 h15 min. The reaction mixture was filtered through celite and rinsed withMeOH and CH₂Cl₂. Flash column chromatography (CH₂Cl₂ to 8% MeOH/CH₂Cl₂)of the residue gave the desired4-({2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethyl}-methyl-amino)-benzoicacid methyl ester in 78% yield (305 mg).

Step 8: The intermediate from step 7 was treated with α-toluenesulfonylchloride according to the procedure in Example 87 step 2 to generate thedesired product in 83% yield.

Step 9: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 91% yield. HRMS calc for[C₃₉H₃₈ClN₃O₄S+H] 692.23444 found 692.23374.

EXAMPLE 1484-[{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

Step 1: The intermediate from example 147 step 7 was treated with3,4-dichlorophenylmethanesulfonylchloride according to the procedure inExample 87 step 2 to generate the desired product in 87% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 68% yield. HRMS calc for[C₄₀H₃₆Cl₃N₃O₄S+H] 760.15649 found 760.1573.

EXAMPLE 1494-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

Step 1: The intermediate from example 147 step 7 was treated with2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure inExample 87 step 2 to generate the desired product in 96% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 88% yield. HRMS calc for[C₄₀H₃₇Cl₂N₃O₄S+H] 726.19546 found 726.19461.

EXAMPLE 1504-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

Step 1: The intermediate from example 147 step 7 was treated with2-chlorobenzenesulfonyl chloride according to the procedure in Example87 step 2 to generate the desired product in 96% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 84% yield. HRMS calc for[C₃₉H₃₅Cl₂N₃O₄S+H] 712.17981 found 712.17966.

EXAMPLE 1514-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid

Step 1: The intermediate from example 147 step 7 was treated with2-methoxy-benzenesulfonyl chloride according to the procedure in Example87 step 2 to generate the desired product in 95% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, to afford the title acid in 73% yield. HRMS calc for[C₄₀H₃₈ClN₃O₅S+H] 708.22935 found 708.2286.

EXAMPLE 1524-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,4-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 95% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 77% yield. HRMS calc forC₃₉H₃₃Cl₃N₂O₄S, 730.1227; found (ESI+), 731.1299.

EXAMPLE 1534-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,6-dichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 93% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 71% yield. HRMS calc forC₃₉H₃₃Cl₃N₂O₄S, 730.1227; found (ESI+), 731.13005.

EXAMPLE 1544-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,4,6-trichlorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 76% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 84% yield. HRMS calc forC₃₉H₃₂Cl₄N₂O₄S, 764.0837; found (ESI+), 765.08981.

EXAMPLE 1554-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-cyanobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 87%yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 and purified by prep HPLC to afford the title acid in 8%yield. HRMS calcd for C₄₀H₃₄ClN₃O₄S, 687.1959; found (ESI+), 688.2019.

EXAMPLE 1564-(3-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}propyl)benzoicacid

Step 1: Methyl4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoate(Example 154, Step 1, 0.43 g, 0.61 mmol) was dissolved in THF (4 mL) andMeOH (12 mL). Cobalt (II) chloride (0.16 g, 1.2 mmol) and NaBH₄ (0.23 g,6.1 mmol) were added. After 2 h the mixture was filtered, concentrated,and chromatographed on silica gel (MeOH—CH₂Cl₂) to afford the aminoester in 13% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 59% yield. HRMS calcd forC₃₉H₃₆ClN₃O₅S, 693.2064; found (ESI+), 694.21261

EXAMPLE 1574-[3-(1-benzhydryl-2-{2-[(1,1′-biphenyl-2-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoicacid

Step 1: 2-Bromobiphenyl (0.55 mL, 3.2 mmol) was dissolved in THF (10 mL)and Et₂O (10 mL) and cooled at −78° .C while n-BuLi (1.3 mL of 2.5 Msolution in hexanes, 3.2 mmol) was added rapidly dropwise. After 40 min,the mixture was added via cannula to a −78° C. solution of SO₂ (10 mL)in Et₂O (20 mL). The mixture was warmed to room temperature overnight,concentrated, and triturated with Et₂O. The resulting white solid wassuspended in hexane (40 mL) and cooled at 0° C. Sulfuryl chloride (3.4mL of 1.0 M soln. in CH₂Cl₂, 3.4 mmol) was added and the mixture wasstirred at room temperature for 5 h. It was then concentrated to afford2-biphenylsulfonyl chloride in 67% yield.

Step 2: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-biphenylsulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 83% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 98% yield. HRMS calcd forC₄₅H₃₉ClN₂O₄S, 738.2319; found (ESI+), 739.23825.

EXAMPLE 1584-{3-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-bromobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 to generate the product in 76%yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calcd forC₃₉H₃₄BrClN₂O₄S, 740.1111; found (ESI+), 741.11696.

EXAMPLE 1594-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,4-dichlorobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 83% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 80% yield. HRMS calc forC₃₈H₃₁Cl₃N₂O₅S, 732.1019; found (ESI+), 733.10824.

EXAMPLE 1604-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,6-dichlorobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 77% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield. HRMS calc forC₃₈H₃₁Cl₃N₂O₅S, 732.1019; found (ESI+), 733.10836.

EXAMPLE 1614-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,4,6-trichlorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 90% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 87% yield. HRMS calcd forC₃₈H₃₀Cl₄N₂O₅S, 766.0630; found (ESI+), 767.07063.

EXAMPLE 1624-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-cyanobenzenesulfonyl chloride according to theprocedure in Example 1 Step 7 in 82% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 and purified by prep HPLC to afford the title acid in 17%yield. HRMS calcd for C₃₉H₃₂ClN₃O₅S, 689.1751; found (ESI+), 690.18082.

EXAMPLE 1634-(2-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: Methyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoate(Example 161, Step 1, 0.31 g, 0.44 mmol) was dissolved in THF (4 mL) andMeOH (12 mL). Cobalt (II) chloride (0.11 g, 0.88 mmol) and NaBH₄ (0.17g, 4.4 mmol) were added. After 2 h the mixture was filtered,concentrated, and chromatographed on silica gel (MeOH—CH₂Cl₂) to affordthe amino ester in 17% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 39% yield. HRMS calcd forC₃₉H₃₆ClN₃O₅S, 693.2064; found (ESI+), 694.21261.

EXAMPLE 1644-[2-(1-benzhydryl-2-{2-[(1,1′-biphenyl-2-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: The sulfonamide was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-biphenylsulfonyl chloride (Step 1, Example156) according to the procedure in Example 1 Step 7 in 93% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calcd forC₄₄H₃₇ClN₂O₅S, 740.2112; found (ESI+), 741.21709.

EXAMPLE 1654-{2-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-bromobenzenesulfonyl chloride according to theprocedure in Example 1 Step 7 in 90% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 91% yield. HRMS calcd forC₃₈H₃₂BrClN₂O₅S, 742.0904; found (ESI+), 743.09697.

EXAMPLE 1664-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 5-chloro-2,4-difluorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 68% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 44% yield. HRMS calc for[C₃₉H₃₂Cl₂F₂N₂O₄S+H] 733.15007 found 733.14978.

EXAMPLE 1674-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methoxy-4-methylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 86% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 39% yield. HRMS calc for[C₄₁H₃₉ClN₂O₅S+H] 707.2341 found 707.23407.

EXAMPLE 1684-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 4-chloro-2,5-difluorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 79% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 63% yield. HRMS calc for[C₃₉H₃₂Cl₂F₂N₂O₄S+H] 733.15007 found 733.14882.

EXAMPLE 1694-{2-[1-Benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 5-chloro-2,4-difluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 38% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 31% yield. HRMS calc for[C₃₈H.₃₀Cl₂F₂N₂O₅.S+H] 735.12933 found 735.12824.

EXAMPLE 1704-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-chloro-2,5-difluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 79% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 63% yield. HRMS calc for[C₃₈H.₃₀Cl₂F₂N₂O₅.S+H] 735.12933 found 735.12913.

EXAMPLE 1714-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methoxy-4-methyl-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7.

Step 2: The crude ester intermediate was hydrolyzed according to Step 8Example 1 to afford 407 mg of the title acid in quantitative yield. HRMScalc for [C₄₀H.₃₇ClN₂O₆.S+H] 709.21337 found 709.21194.

EXAMPLE 1724-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazole according to theprocedure in Example 1 Step 7 to generate the product in 43% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 26% yield after HPLC separation.HRMS calc for [C₃₉H₃₂Cl₂N₄O₅S+H] 739.15433 found 739.1537.

EXAMPLE 1734-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added7-methoxy-benzo[1,2,5]oxadiazole-4-sulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 43% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 36% yield after HPLC separation.HRMS calc for [C₄₀H₃₅ClN₄O₆S+H] 735.2046 found 735.2029.

EXAMPLE 1744-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazoleaccording to the procedure in Example 1 Step 7 in 56% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 30% yield after HPLC separation.HRMS calc for [C₃₆H.₃₀Cl₂N₄O₆.S+H] 741.1343 found 741.1328.

EXAMPLE 1754-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-chloro-7-chlorosulfonyl-2,1,3-benzoxadiazoleaccording to the procedure in Example 1 Step 7 in 56% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 36% yield after HPLC separation.HRMS calc for [C₃₉H.₃₃ClN₄O₇.S+H] 737.1838 found 737.1819.

EXAMPLE 1764-(3-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)thien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added5-(2-methyl-1,3-thiazol-4-yl)-thiophene-2-sulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 90% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₁H₃₆ClN₃O₄S₃+H] 766.1636 found 766.1629.

EXAMPLE 1774-(2-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)thien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and5-(2-methyl-1,3-thiazol-4-yl)-thiophene-2-sulfonyl chloride according tothe procedure in Example 1 Step 7 in 100% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₄₀H₃₄ClN₃O₅.S₃—H] 767.1269 found 766.1259.

EXAMPLE 1784-[2-(1-benzhydryl-5-chloro-2-{2-[(thien-3-ylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-thiophenesulfonyl chloride according to theprocedure in Example 1 Step 7 in 91% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₆H₃₁ClN₂O₅.S₂+H] 671.14357 found 671.1428.

EXAMPLE 1794-{2-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 6-morpholino-3-pyridinesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 91% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₄₁H₃₉ClN₄O₆.S+H] 751.23516 found 751.2345.

EXAMPLE 1804-[3-(1-benzhydryl-5-chloro-2-{2-[(thien-3-ylsulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 3-thiophenesulfonyl chloride according tothe procedure in Example 1 Step 7 to generate the product in 87% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₃₇H₃₃ClN₂O₄S₂+H] 669.16431 found 669.1629.

EXAMPLE 1814-{3-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 6-morpholino-3-pyridinesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 79% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₄₂H₄₁ClN₄O₅S+H] 749.2559 found 749.255.

EXAMPLE 1824-(2-{1-Benzhydryl-2-[2-(benzo[1,2,5]oxadiazole-4-sulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and isoxazolo[4,5-c]pyridine-4-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 88% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₈H₃₁ClN₄O₆S+H] 707.17256 found 707.1719.

EXAMPLE 1834-(3-{1-Benzhydryl-2-[2-(benzo[1,2,5]oxadiazole4-sulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added isoxazolo[4,5-c]pyridine-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 69% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. HRMS calc for[C₃₉H₃₃ClN₄O₅S+H] 705.1933 found 705.1931.

EXAMPLE 1844-(2-{1-Benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-benzyloxy-benzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 87% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calc for[C₄₅H₃₉ClN₂O₆S−H] 769.21446 found 769.2129.

EXAMPLE 1854-(2-{1-Benzhydryl-5-chloro-2-[2-(2-isopropoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-isopropoxybenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 88% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 74% yield after trturation withethylether. HRMS calc for [C₄₁H₃₉ClN₂O₆S+H] 723.22902 found 723.2284.

EXAMPLE 1864-(3-{1-Benzhydryl-5-chloro-2-[2-(2-isopropoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-isopropoxybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 71% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield after HPLC purification.HRMS calc for [C₄₂H₄₁ClN₂O₅S+H] 721.24975 found 721.2490.

EXAMPLE 1874-(3-{1-Benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-benzyloxy-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 57% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield after HPLC purification.HRMS calc for [C₄₆H₄₁ClN₂O₅S+H] 769.2505 found 769.2494.

EXAMPLE 1884-(3-{1-Benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid

Step 1: The benzyl group from step 1 Example 186 was removed byhydrogenolysis. The crude was purified on silica gel column withCH₂Cl₂-5% EtOAc/CH₂Cl₂, to get a mixture which was further purified byHPLC to obtain4-(3-{1-Benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester (7%) and4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester (18%) Step 2: The4-(3-{1-Benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 81% yield. HRMS calc for[C₃₉H₃₆N₂O₅S+H] 645.2418 found 645.2423.

EXAMPLE 1894-(3-{1-Benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid

Step 1:4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid methyl ester intermediate from step 1 of Example 188 was hydrolyzedaccording to Step 8 Example 1 to afford the title acid in 86% yield.HRMS calc for [C₃₉H₃₅ClN₂O₅S+H] 679.2028 found 679.2038.

EXAMPLE 1904-(2-{1-Benzhydryl-5-chloro-2-[2-(2-chloro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoicacid

Step 1: To a solution of Ph3P (698 mg, 2.7 mmole, 2.0 equiv.) in THF (10ml) was slowly introduced diisopropylazodicarboxylate (0.55 ml, 2.7mmole, 2.0 equiv.) at 0° C. under N₂. It was allowed to stir for 15 min.A solution of2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(859 mg, 1.3 mmole, 1.0 equiv. Step 6, Example 142) in THF (5 ml) wastransferred to Mitsunobu reagents, followed by2-fluoro-4-hydroxy-benzoic acid methyl ester (340 mg, 2.0 mmole, 1.5equiv.). The resulted solution was stirred overnight. THF was removed.The residues were partitioned between EtOAc and water. The organic phasewas washed with water and brine, dried over MgSO₄. The product waspurified on silica gel column with 8% EtOAc/hexane. 0.95 g (90%) ofproduct was obtained as a white solid.

Step 2: The4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoicacid methyl ester was deprotected according to the procedure in Example142, step 9 to yield4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester in 89% yield.

Step 3:4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester was activated by conversion to the mesylate followingthe procedure in Step 10 Example 142 and the resulting product was usedcrude in the next step.

Step 4: The mesylate from above was displaced with azide as described inStep 11 Example 142 to generate4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester in 97% yield (over two steps).

Step 5: The4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoicacid methyl ester was reduced under Staudinger conditions to yieldmethyl4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoatein 93% yield.

Step 6: The methyl4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoatefrom above and 2-chloro-benzenesulfonyl chloride were reacted accordingto the procedure in Example 1 Step 7 to generate the desired product in73% yield.

Step 7: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₈H₃₁Cl₂FN₂O₅S+H] 717.13876 found 717.1365.

EXAMPLE 1914-(2-{1-Benzhydryl-5-chloro-2-[2-(2-chloro-6-methyl-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoicacid

Step 2: This compound was prepared from methyl4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoate(Step 5, Example 189) and 2-chloro-6-methyl-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 66% yield.

Step 3: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield HRMS calc for[C₃₉H₃₃Cl₂FN₂O₅S+H] 731.15441 found 731.1532.

EXAMPLE 192N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)methanesulfonamide

Step 1: The2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142) was coupled with 4-Hydroxy-benzonitrile accordingto the conditions described in Example 189, Step 1 to yield4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzonitrilein 85% yield.

Step 2: The silyl ether from above was deprotected following the Example142, step 9 to yield4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzonitrilein 93% yield.

Step 3: The alcohol from above was activated by conversion to themesylate as described in Step 10 Example 142 to yield the desiredmesylate which was used without purification in the next step.

Step 4: The mesylate from above was treated under the conditionsdescribed in Step 11 Example 142 to generate4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzonitrilein 91% yield (2 steps).

Step 5:4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzonitrilewas reduced under Staudinger conditions as detailed in Step 12, example142 to yield4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzonitrilein 92% yeild.

Step 6: The4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrilefrom above and (3,4-dichloro-phenyl)-methanesulfonyl chloride werereacted according to the procedure in Example 1 Step 7 to yield thedesired product in 92% yield.

Step 7: The mixture of nitrile (1.0 equiv.), azidotrimethylsilane (2.0equiv.), dibutyltin oxide (0.1 equiv.) and toluene (3.3 ml/mmole) in asealed tube was heated at 120° C. for 20 hours. It was acidified with 1N HCl at room temperature, then diluted with EtOAc. The organic phasewas washed with water and brine, dried over MgSO₄. The crude tetrazolewas chromatographed with 50% EtOAc/hexanes−80% EtOAc/hexanes plus 0.5%of acetic acid to afford the title product in 58% yield HRMS calc for[C₃₉H₃₃Cl₃N₆O₃S+H] 771.14732 found 771.1475.

EXAMPLE 193N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)phenoxy]-ethyl}-1H-indol-2-yl)-ethyl]-2-chlorobenzenesulfonamide

Step 1:4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrile(Step 5, Example 191) and 2-chloro-benzenesulfonyl chloride were reactedaccording to the procedure in Example 1 Step 7 to yield the desiredproduct in 77% yield.

Step 2: The nitrile from above was converted to tetrazole according toStep 7 of Example 191 to afford the title product in 45% yield. HRMScalc for [C₃₈H₃₂Cl₂N₆O₃S+H] 723.17065 found 723.1711.

EXAMPLE 194N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]butane-1-sulfonamide

Step 1: The4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrile(Step 5, Example 191) and 1-butanesulfonyl chloride where reactedaccording to the procedure in Example 1 Step 7 to yield the product in79% yield.

Step 2: The nitrile was converted to tetrazole according to Step 7 ofExample 191 to afford the title product in 91% yield HRMS calc for[C₃₆H₃₇ClN₆O₃S+H] 669.24092 found 669.2409.

EXAMPLE 195N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2,2,2-trifluoroethanesulfonamide

Step 1: The4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}benzonitrile(Step 5, Example 191) and 2,2,2-trifluoro-ethanesulfonyl chloride wherereacted according to the procedure in Example 1 Step 7 to yield thedesired product in 64% yield.

Step 2: The nitrile was converted to tetrazole according to Step 7 ofExample 191 to afford the title product in 77% yield HRMS calc for[C₃₄H₃₀ClF₃N₆O₃S+H] 695.18135 found 695.1807.

EXAMPLE 1964-(2-{1-Benzhydryl-5-chloro-2-[2-(2,4,6-trifluoro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,4,6-trifluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 92% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₃₈H₃₀ClFN₂O₃S+H] 719.15889 found 719.15843.

EXAMPLE 1974-(2-{1-Benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-methoxy-2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 74% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 94% yield. HRMS calc for[C₃₉H₃₄ClN₃O₈S+H] 740.1828 found 740.1834.

EXAMPLE 1984-(2-{1-Benzhydryl-5-chloro-2-[2-(3-trifluoromethoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-(trifluoromethoxy)benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 86% yield. HRMS calc for[C₃₉H₃₂ClF₃N₂O₆S+H] 771.1514 found 771.1512.

EXAMPLE 1994-(3-{1-Benzhydryl-5-chloro-2-[2-(2,4,6-trifluoro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl)-propyl)-benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,4,6-trifluorobenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield. HRMS calc for[C₃₉H₃₂ClF₃N₂O₄S+H] 717.17962 found 717.17913.

EXAMPLE 2004-(3-{1-Benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 4-methoxy-2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 81% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 95% yield. HRMS calc for[C₄₀H₃₆ClN₃O₇S+H] 738.2035 found 738.2028.

EXAMPLE 2014-(3-{1-Benzhydryl-5-chloro-2-[2-(3-trifluoromethoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 3-(trifluoromethoxy)benzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 83% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 91% yield. HRMS calc for[C₄₀H₃₄ClF₃N₂O₅S+H] 747.19019 found 747.18996.

EXAMPLE 2024-(3-{1-Benzhydryl-5-chloro-2-[2-({[4-(methysulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 4-methysulfonybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₆S₂ +H] 741.18544 found 741.18421.

EXAMPLE 203 4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-methylsulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-methylsulfonylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H.₃₅ClN₂O₇S₂−H] 741.15014 found 741.14842.

EXAMPLE 2044-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(methysulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methylsulfonybenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₆S₂+H] 741.18544 found 741.18425.

EXAMPLE 2054-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(methylsulfonyl)phenyl]sulfonyl}amino)ethyl]1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methylbenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H.₃₅ClN₂O₇S₂+H] 743.16470 found 743.16431.

EXAMPLE 2064-[3-(1-Benzhydryl-2-{2-[(1,1′-biphenyl-3-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 3-phenylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₅H₃₉ClN₂O₄S+H] 739.23919 found 739.23896.

EXAMPLE 2074-[2-(1-benzhydryl-2-{2-[(1,1′-biphenyl-3-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-phenylbenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₄H.₃₇ClN₂O₅S+H] 741.21845 found 741.21879.

EXAMPLE 2084-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and2-trifluoromethylsulfonybenzenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₄F₃ClN₂O₅S+H] 731.19527 found 731.19591.

EXAMPLE 2094-(2-{1-benzhydryl-5-chloro-2-[2({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-trifluoromethylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₀H₃₄F₃ClN₂O₄S₂+H] 733.17454 found 733.17439.

EXAMPLE 2104-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 5-Methyl-1-phenyl-1H-pyrazole-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 93% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 99% yield. HRMS calc for[C₄₃H₃₉ClN₄O₄S+H] 743.24533 found 743.24506.

EXAMPLE 2114-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 5-Methyl-1-phenyl-1H-pyrazole-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 88% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₃₇ClN₄O₅S+H] 745.2246 found 745.22362.

EXAMPLE 2124-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 1 ,5-Dimethyl-1H-pyrazole-4-sulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 92% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₃₉H₃₉ClN₄O₄S+H] 695.24533 found 695.24453.

EXAMPLE 2134-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 100% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 74% yield. HRMS calc for[C₃₈H₃₇ClN₄O₅S+H] 697.2246 found 697.2241.

EXAMPLE 2144-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2,3-Dichloro-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 85% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 96% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₄S −H] 729.1154 found 729.1135.

EXAMPLE 2154-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To the4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) was added 2,3-Dichloro-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 79% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield. HRMS cale for[C₃₈H₃₁Cl₃N₂O₅S −H] 731.0947 found 731.0930.

EXAMPLE 2164-{3-[1-benzhydryl-5-chloro-2-(2-{[(4′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 4′-fluorophenyl-4-benzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₅H₃₈ClFN₂O₄S+H] 757.22976 found 757.22874.

EXAMPLE 2174-{2-[1-benzhydryl-5-chloro-2-(2-{[(4′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4′-fluorophenyl-4-benzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₄H₃₆ClFN₂O₅S+H] 759.20903 found 759.20745.

EXAMPLE 2184-(3-{1-Benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 3-trifluoromethylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClF₃N₂O₄S+H] 731.19527 found 731.19582.

EXAMPLE 2194-(2-{1-benzhydryl-5-chloro-2-[2-({[3-trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-trifluoromethylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClF3N₂O₅S+H] 733.17454 found 733.17431.

EXAMPLE 2204-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step 1, was added 3,4-dichlorothiophenol according to theprocedure in Example 81 step 2. The crude was purified by thepreperative HPLC in 24% yield of ester and 14% of acid.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 97% yield. m/z (M−1) 779.01.

EXAMPLE 2214-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3-chloro-4-fluorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step 1, was added 3-chloro-4-flurothiophenol according to theprocedure in Example 81 step 2. The product was purified by flash columnwith 30% EtOAc/hexanes in 70% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. m/z (M−1) 760.94.

EXAMPLE 2224-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-fluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-fluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₉H₃₄ClFN₂O₄S+H] 681.19846 found 681.19854.

EXAMPLE 2234-{2-[1-benzhydryl-5-chloro-2-(2-{[3-fluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-fluorobenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₈H₃₃ClFN₂O₅S+H] 683.17773 found 683.17694.

EXAMPLE 224 4-{3-[5-Chloro-2-(2-{[(2,6-difluorophenyl)sulfonyl]amino}ethyl)-1(diphenylmethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2,6-difluorobenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₃₉H₃₃ClF₂N₂O₄S+H] 699.18904 found 699.18850.

EXAMPLE 2254-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-fluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,6-difluorobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₈H₃₂ClF₂N₂O₅S+H] 701.16831 found 701.16849.

EXAMPLE 2264-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-chloro-6-methylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S+H] 711.18456 found 711.18404.

EXAMPLE 227 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-chloro-6-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂O₅S+H] 713.16383 found 713.16269.

EXAMPLE 2284-(3-{1-Benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 4-trifluoromethylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClF₃N₂O₄S+H] 731.19527 found 731.19580.

EXAMPLE 2294-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 4-trifluoromethylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClF₃N₂O₅S+H] 733.17454 found 733.17432.

EXAMPLE 2304-(3-{5-Chloro-1-(diphenylmethyl)-2-[2{[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-trifluoromethoxybenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClF₃N₂O₅S+H] 747.19019 found 747.18848.

EXAMPLE 2314-(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-trifluoromethoxybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClF₃N₂O₆S+H] 749.16945 found 749.16813.

EXAMPLE 2324-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₄S+H] 677.22354 found 677.22244.

EXAMPLE 233 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methylbenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S+H] 679.20280 found 679.20197.

EXAMPLE 234 4-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-methoxybenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₅S+H] 693.2185 found 693.21852.

EXAMPLE 235 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methoxybenzenesulfonyl chloride according tothe procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₆S+H] 695.19722 found 695.19701.

EXAMPLE 236 4-{3-[1-Benzhydryl-2(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-tert-butylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₃H₄₃ClN₂O₄S+H] 719.27049 found 719.27057.

EXAMPLE 2374-{2-[1-benzhydryl-2-(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-tert-butylbenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₄₂H₄₁ClN₂O₅S+H] 721.24975 found 721.24907.

EXAMPLE 238 4-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-20yl]propyl}benzoate (Step 6, Example 42) was added and2-methylthiobenzenesulfonyl chloride according to the procedure inExample 1 Step 7 to generate the product in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₇ClN₂O₄S₂+H] 25 709.19561 found 709.19504.

EXAMPLE 239 4-(2-{1-benzhydryl-5-chloro-2-({[2-(methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-methylthiobenzenesulfonyl chloride accordingto the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S₂+H] 711.17487 found 711.17518.

EXAMPLE 240 4-{3-[1-Benzhydryl-5-chloro-2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 3-chloro-2-methylbenzenesulfonylchloride according to the procedure in Example 1 Step 7 to generate theproduct in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₀H₃₆Cl₂N₂O₄S+H] 711.18456 found 711.18465.

EXAMPLE 241 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 3-chloro-2-methylbenzenesulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₄Cl₂N₂O₅S+H] 713.16383 found 713.16296.

EXAMPLE 2424-[2-(2-{2-[2-(4-Acetyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87,Step 1 and 1-acetylpiperazine according to the procedure in Example 87,Step 2 except that it was heated at 60° C. for 19 h in 91% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to the title acid in 19% yield. m/z (M−1) 741.2

EXAMPLE 2434-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87,Step 1 and cis-2,6-dimethylpiperazine according to the procedure inExample 87, Step 2 except that it was heated at 60° C. for 19 h in 97%yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to the title acid in 39% yield. m/z (M−1) 727.2

EXAMPLE 2444-[2-(2-{2-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: To a solution of4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid methyl ester (Step 1, Example above) (31 mg, 0.042 mmol) in CH₂Cl₂(1 mL) at 0° C. were added Et₃N (0.10 mL) and Ac₂O (60 uL) and thereaction mixture was stirred at rt for 4 h. Aqueous workup followed bysilica gel chromatography (3.5% MeOH/MeOH) gave the desired esterintermediate (17 mg, 52% yield).

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to the title acid in 96% yield. m/z (M−1) 771.2.

EXAMPLE 2454-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87,Step 1 and 1-acetylpiperazine 4-methylpiperidine according to theprocedure in Example 87, Step 2. The product was purified by the flashcolumn with 50-60% EtOAc/hexane in 87% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 91% yield. m/z (M−1) 712.3.

EXAMPLE 2464-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87,Step 1 and 3-methylpiperidine according to the procedure in Example 87,Step 2. The product was purified by the flash column with 50-60%EtOAc/hexane in 94% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 87% yield. HRMS calc for [C₄₀H₄₄ClN₃O₅S+H] 714.2763 found714.2765.

EXAMPLE 2474-[2-(1-Benzhydryl-2-{2-[2-(2-carbamoyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-5-chloro-1H-indol-3-yl)-ethoxy]-benzoicacid

Step 1: The compound was prepared from the intermediate from Example 87,Step 1 and L-prolinamide according to the procedure in Example 87, Step2. The product was purified by the flash column with EtOAc in 86% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 43% yield after preparative HPLC purification. HRMS calc for[C₃₉H₄₁ClN₄O₆S+H] 729.2508 found 729.251.

EXAMPLE 2484-[2-(1-benzhydryl-5-chloro-2-(2-[({2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: The compound was prepared from the intermediate Example 87, Step1 and (S)-(+)-2-(methoxymethyl)pyrrolidine according to the procedureExample 87, Step 2. The product was purified by the flash column with80% EtOAc/hexane in 87 % yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 87% yield. HRMS calc for [C₄₀H₄₄ClN₃O₆S+H] 730.2712 found730.2709.

EXAMPLE 2494-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-ethylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl)ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 100step 1 and 2-ethylpiperidine according to the procedure in Example 100step 2. The product was purified by the flash column with 50-60%EtOAc/hexane in 73% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 38% yield after preparative HPLC purification. HRMS calc for[C₄₁H₄₆ClN₃O₅S+H] 728.292 found 728.2925.

EXAMPLE 2504-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(3R,5S)-3,5-dimethylmorpholin4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: The compound was prepared from the intermediate from Example 100step 1 and cis-2,6-dimethylmorpholine according to the procedure Example100 step 2. The product was purified by the flash column with 50%EtOAc/hexane in 79% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 94% yield. m/z (M−1) 729.4

EXAMPLE 2514-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 100step 1 and (1S, 4S)-(+)-2-aza-5-oxabicyclo-[2.2.1]-heptane hydrochlorideaccording to the procedure in Example 100 step 2. The product waspurified on the CombiFlash with 1-7% MeOH/CH₂Cl₂ in 85% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 100% yield. HRMS calc for [C₃₉H₄₀ClN₃O₆S+H] 714.2399 found714.2397.

EXAMPLE 2524-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-isopropylpyrrolidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from Example 100step 1 and 2-(methylethyl)-pyrrolidine hydrochloride according to theprocedure Example 100 step 2. The product was purified on the CombiFlashwith 1-5% MeOH/CH₂Cl₂ in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 97% yield. HRMS calc for [C₄₁H₄₆ClN₃O₅S+H] 728.292 found728.293.

EXAMPLE 2534-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopiperazin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: The compound was prepared from the intermediate from fromExample 87, Step 1 and 3-methyl-2-piperazinone according to theprocedure in Example 87, Step 2. The product was purified by the flashcolumn with 5% MeOH/CH₂Cl₂ in 80% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1, except that the pH was adjusted to 4-5, to afford the titleacid in 29% yield after preparative HPLC purification. HRMS calc for[C₃₉H₄₁ClN₄O₆S+H] 729.2508 found 729.2501.

EXAMPLE 2544-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-chlorobenzenesulfonyl chlorideaccording to the procedure in Example 1, Step 7 to generate the productin 66% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.94 (m, 2H), 2.74 (m, 6H),2.97 (m, 2H), 3.91 (s, 3H), 4.94 (t, J=6.32 Hz, 1H), 6.48 (d, J=9.09 Hz,1H), 6.79 (dd, J=8.84, 2.02 Hz, 1H), 6.83 (s, 1H), 7.03 (m, 4H), 7.26(m, 9H), 7.39 (d, J=2.02 Hz, 1H), 7.44 (d, J=3.54 Hz, 2H), 7.90 (d,J=7.58 Hz, 1H), 7.96 (d, J=8.34 Hz, 2H)

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford, after flash chromatography, the title acid in 84%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.96 (m, 2H), 2.76 (m, 6H), 2.98(m, 2H), 5.00 (t, J=6.32 Hz, 1H), 6.79 (dd, J=8.84, 2.02 Hz, 1H), 6.84(s, 1H), 7.04 (m, 4H), 7.28 (m, 10H), 7.40 (d, J=1.77 Hz, 1H), 7.45 (d,J=3.79 Hz, 2H), 7.90 (d, J=7.58 Hz, 1H), 8.02 (d, J=8.34 Hz, 2H). HRMScalc for C₃₉H₃₄Cl₂N₂O₄S Na, 719.1514; found (ESI−), 695.15363

EXAMPLE 2554-{2-[1-benzhydryl-5-chloro-2-(2-{([(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 2-chlorobenzenesulfonyl chloride according to the procedure inExample 1, Step 7 in 86% yield. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.93 (m,2H), 3.02 (m, 2H), 3.11 (t, J=6.57 Hz, 2H), 3.81 (s, 3H), 4.19 (t,J=6.57 Hz, 2H), 6.49 (d, J=8.84 Hz, 1H), 6.80 (dd, J=8.84, 2.02 Hz, 1H),6.96 (d, J=8.84 Hz, 2H), 7.01 (s, 1H), 7.04 (dd, J=6.95, 2.40 Hz, 4H),7.34 (m, 5H), 7.40 (m, 1H), 7.60 (m, 3H), 7.80 (dd, J=7.83, 1.52 Hz,1H), 7.86 (d, J=8.84 Hz, 2H), 8.11 (t, J=5.81 Hz, 1H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1. The crude material was purified via flash chromatography toafford the title acid in 74% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.89(m, 2H), 3.18 (t, J=6.57 Hz, 2H), 4.20 (t, J=6.57 Hz, 2H), 5.09 (t,J=6.32 Hz, 1H), 6.53 (d, J=8.84 Hz, 1H), 6.82 (m, 3H), 6.90 (s, 1H),7.05 (m, 4H), 7.26 (m, 7H), 7.45 (m, 2H), 7.52 (d, J=2.02 Hz 1H), 7.90(m, 1H), 8.00 (d, J=8.84 Hz, 2H). HRMS calc for C₃₈H₃₂Cl₂N₂O₅S,698.1409; found (ESI+), 699.14786. Anal. Calcd for C₃₈H₃₂Cl₂N₂05S: C,65.23; H, 4.61; N, 4.00. Found: C, 65.02; H, 4.44; N, 3.94.

EXAMPLE 2564-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid

Step 1: This compound was prepared from4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-benzoicacid methyl ester and 2-chlorobenzensulfonyl chloride according to theprocedure in Example 1, Step 7 in 48% yield. ¹H NMR (400 MHz, CDCl₃) δppm 2.88 (q, J=7.07 Hz, 2H), 3.03 (t, J=7.33 Hz, 2H), 3.20 (m, 2H), 3.43(m, 2H), 3.97 (s, 3H), 5.18 (t, J=6.44 Hz, 1H), 6.46 (d, J=8.84 Hz, 1H),6.78 (dd, J=8.97, 2.15 Hz, 1H), 6.84 (s, 1H), 7.04 (dd, J=6.69, 2.40 Hz,4H), 7.21 (d, J=2.02 Hz, 1H), 7.31 (m, 7H), 7.48 (d, J=3.79 Hz, 2H),7.91 (d, J=7.58 Hz, 1H), 8.08 (d, J=8.59 Hz, 2H), 8.24 (m, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 97% yield. ¹H NMR (400 MHz, CDCl₃)δ ppm 2.88 (q, J=6.91 Hz, 2H), 3.04 (t, J=7.20 Hz, 2H), 3.22 (m, 2H),3.45 (m, 2H), 5.25 (t, J=6.44 Hz, 1H), 6.47 (d, J=9.09 Hz, 1H), 6.78(dd, J=8.84, 2.02 Hz, 1H), 6.84 (s, 1H), 7.04 (dd, J=6.57, 2.53 Hz, 4H),7.22 (d, J=2.02 Hz, 1H), 7.31 (m, 7H), 7.48 (d, J=3.79 Hz, 2H), 7.92 (d,J=7.83 Hz, 1H), 8.12 (d, J=8.59 Hz, 2H), 8.28 (d, J=8.34 Hz, 2H).

EXAMPLE 2574-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 1,2-dimethylimidazole-4-sulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 80% yield. ¹HNMR (400 MHz, DMSO-D6) δ ppm 1.86 (m, 2H), 2.18 (s, 3H), 2.71 (m, 4H),2.94 (m, 4H), 3.49 (s, 3H), 3.83 (s, 3H), 6.42 (d, J=8.84 Hz, 1H), 6.76(dd, J=8.84, 2.02 Hz, 1H), 7.06 (m, 4H), 7.36 (m, 8H), 7.44 (d, J=2.02Hz, 1H), 7.49 (s, 1H), 7.59 (s, 1H), 7.87 (d, J=8.08 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 61% yield. ¹H NMR (400 MHz,DMSO-D6) δ ppm 1.87 (m, 2H), 2.18 (s, 3H), 2.70 (t, J=7.58 Hz, 4H), 2.95(m, 4H), 3.49 (s, 3H), 6.42 (d, J=8.84 Hz, 1H), 6.76 (dd, J=8.84, 2.02Hz, 1H), 7.06 (m, 5H), 7.35 (m, 8H), 7.44 (d, J=2.02 Hz, 1H), 7.49 (s,1H), 7.59 (t, J=4.93 Hz, 1H), 7.85 (d, J=8.34 Hz, 2H). HRMS: calcd forC₃₈H₃₇ClN₄O₄S, 680.2224; found (ESI+), 681.22879

EXAMPLE 2584-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 1,2-dimethylimidazole-4-sulfonyl chloride according to the procedurein Example 1, Step 7 in 84% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.25(s, 3H), 3.07 (m, 2H), 3.13 (m, 2H), 3.18 (t, J=6.82 Hz, 2H), 3.39 (s,3H), 3.88 (s, 3H), 4.17 (t, J=6.69 Hz, 2H), 5.30 (m, J=2.78 Hz, 1H),6.47 (d, J=9.09 Hz, 1H), 6.79 (dd, J=8.84, 2.02 Hz, 1H), 6.83 (d, J=8.84Hz, 2H), 6.93 (s, 1H), 7.08 (m, 5H), 7.29 (m, 6H), 7.51 (d, J=2.02 Hz,1H), 7.94 (d, J=8.84 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 55% yield. ¹H NMR (400 MHz,DMSO-D6) δ ppm 2.17 (s, 3H), 3.02 (m, J=9.10 Hz, 4H), 3.14 (t, J=6.57Hz, 2H), 3.47 (s, 3H), 4.21 (t, J=6.69 Hz, 2H), 6.47 (d, J=8.84 Hz, 1H),6.79 (dd, J=8.84, 2.27 Hz, 1H), 6.96 (d, J=8.84 Hz, 2H), 7.07 (m, 5H),7.36 (m, 6H), 7.49 (s, 1H), 7.63 (m, 2H), 7.84 (d, J=8.84 Hz, 2H). HRMS:calcd. for C₃₇H₃₅ClN₄O₅S, 682.2017; found (ESI+), 683.20812.

EXAMPLE 2593-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl}propanoicacid

Step 1: This compound was prepared from3-(4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-phenyl)-propionicacid ethyl ester and 2-chlorobenzensulfonyl chloride according to theprocedure in Example 1, Step 7 in 78% yield. ¹H NMR (400 MHz, CDCl₃) δppm 1.25 (m, 3H), 2.66 (t, J=7.58 Hz, 2H), 2.88 (q, J=6.48 Hz, 2H), 3.07(m, 6H), 3.34 (m, 2H), 4.12 (q, J=7.07 Hz, 2H), 5.31 (t, J=6.32 Hz, 1H),6.45 (d, J=8.84 Hz, 1H), 6.77 (dd, J=8.84, 2.02 Hz, 1H), 6.85 (s, 1H),7.04 (m, 4H), 7.16 (d, J=1.77 Hz, 1H), 7.30 (m, 7H), 7.46 (m, 4H), 7.91(m, 3H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford, after flash chromatography, the title acid in 41%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.74 (s, 4H), 2.86 (t, J=6.69 Hz,2H), 2.93 (m, 2H), 3.08 (t, J=6.57 Hz, 2H), 3.29 (m, 2H), 6.43 (d,J=8.84 Hz, 1H), 6.61 (s, 1H), 6.78 (m, 2H), 7.00 (m, 4H), 7.25 (m, 7H),7.36 (d, J=1.77 Hz, 1H), 7.45 (m, 2H), 7.50 (d, J=8.34 Hz, 2H), 7.80 (d,J=7.58 Hz, 1H), 7.93 (d, J=8.34 Hz, 2H). HRMS: calcd. forC₄₀H₃₆Cl₂N₂O₆S₂(M−H) 773.1319 found 773.13107.

EXAMPLE 2604-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 3-chloro-4-methylbenzenesulfonyl chloride according to the procedurein Example 1, Step 7 in 100% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.38(s, 3H), 2.92 (q, J=6.99 Hz, 2H), 3.09 (t, J=7.58 Hz, 2H), 3.18 (t,J=6.44 Hz, 2H), 3.88 (s, 3H), 4.21 (t, J=6.44 Hz, 2H), 4.42 (t, J=6.44Hz, 1H), 6.54 (d, J=8.84 Hz, 1H), 6.79 (m, 2H), 6.83 (dd, J=8.84, 2.02Hz, 1H), 6.88 (s, 1H), 7.04 (m, 4H), 7.20 (d, J=8.08 Hz, 1H), 7.29 (m,6H), 7.40 (dd, J=7.96, 1.89 Hz, 1H), 7.52 (d, J=2.02 Hz, 1H), 7.66 (d,J=1.77 Hz, 1H), 7.93 (m, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1. The crude product was purified using flash chromatography toafford the title acid in 69% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.38(s, 3H), 2.93 (m, 2H), 3.10 (t, J=7.45 Hz, 2H), 3.19 (t, J=6.44 Hz, 2H),4.23 (t, J=6.44 Hz, 2H), 4.52 (s, 1H), 6.54 (d, J=8.84 Hz, 1H), 6.83 (m,3H), 6.89 (s, 1H), 7.04 (m, 4H), 7.20 (d, J=8.08 Hz, 1H), 7.29 (m, 6H),7.40 (dd, J=8.08, 1.77 Hz, 1H), 7.53 (d, J=2.02 Hz, 1H), 7.67 (d, J=2.02Hz, 1H), 7.98 (d, J=8.84 Hz, 2H). HRMS: calcd. for C₃₉H₃₄Cl₂N₂O₅S,712.1565; found (ESI+), 713.16268. Anal. Calcd for C₃₉H₃₄Cl₂N₂O₅S: C,65.64; H, 4.80; N, 3.93. Found: C, 65.62; H, 4.52; N, 3.73.

EXAMPLE 2614-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 3-chloro-4-methylbenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 98% yield. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.95 (m, 2H), 2.40 (s, 3H), 2.72 (q, J=8.25Hz, 4H), 2.82 (q, J=6.74 Hz, 2H), 2.96 (t, J=7.33 Hz, 2H), 3.91 (s, 3H),4.27 (t, J=6.44 Hz, 1H), 6.49 (d, J=8.84 Hz, 1H), 6.80 (dd, J=8.97, 2.15Hz, 1H), 6.82 (s, 1H), 7.02 (m, 4H), 7.26 (m, 9H), 7.38 (dd, J=7.96,1.89 Hz, 1H), 7.40 (d, J=2.02 Hz, 1H), 7.66 (d, J=1.77 Hz, 1H), 7.96 (d,J=8.34 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford, after flash chromatography, the title acid in 40%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.96 (m, 2H), 2.40 (s, 3H), 2.73(m, 4H), 2.83 (m, 2H), 2.98 (t, J=7.33 Hz, 2H), 4.33 (t, J=6.32 Hz, 1H),6.49 (d, J=8.84 Hz, 1H), 6.80 (dd, J=8.84, 2.27 Hz, 1H), 6.83 (s, 1H),7.02 (m, 4H), 7.21 (d, J=7.83 Hz, 1H), 7.29 (m, 8H), 7.39 (m, 2H),7.66(d, J=1.77 Hz, 1H), 8.00 (d, J=8.08 Hz, 2H). HMRS: calcd. forC₄₀H₃₆Cl₂N₂O₄S, 710.1773; found (ESI+), 711.18411. Anal. Calcd forC₄₀H₃₆Cl₂N₂O₄S: C, 67.51; H, 5.10; N, 3.94. Found: C, 67.67; H, 5.27; N,3.81.

EXAMPLE 2624-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 3-chloro-5-fluoro-2-methylbenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 in 100% yield. ¹H NMR (400 MHz, CDCl₃) δppm 2.26 (s, 3H), 2.99 (m, 2H), 3.10 (m, 2H), 3.18 (t, J=6.57 Hz, 2H),3.88 (s, 3H), 4.21 (t, J=6.57 Hz, 2H), 4.71 (t, J=6.32 Hz, 1H), 6.52 (d,J=8.84 Hz, 1H), 6.81 (m, 3H), 6.88 (s, 1H), 7.04 (m, 4H), 7.14 (d,J=9.60 Hz, 1H), 7.29 (m, 6H), 7.52 (d, J=2.02 Hz, 1H), 7.58 (d, J=7.58Hz, 1H), 7.94 (m,2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 69% yield. ¹H NMR (400 MHz, CDCl₃)δ ppm 2.26 (s, 3H), 2.99 (m, 2H), 3.11 (m, 2H), 3.19 (t, J=6.44 Hz, 2H),4.23 (t, J=6.44 Hz, 2H), 4.79 (t, J=6.32 Hz, 1H), 6.52 (d, J=8.84 Hz,1H), 6.83 (m, 3H), 6.88 (s, 1H), 7.04 (m, 4H), 7.15 (d, J=9.60 Hz, 1H),7.29 (m, 6H), 7.52 (d, J=2.02 Hz, 1H), 7.59 (d, J=7.58 Hz, 1H), 7.99 (d,J=8.84 Hz, 2H). HRMS: calcd. for C₃₉H₃₃Cl₂FN₂O₅S, 730.1471; found(ESI+), 731.1532.

EXAMPLE 2634-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoateadded and 3-chloro-5-fluoro-2-methylbenzenesulfonyl chloride accordingto the procedure in Example 1, Step 7 to generate the product in 75%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.95 (m, 2H), 2.27 (s, 3H), 2.72(q, J=7.58 Hz, 4H), 2.89 (t, J=6.82 Hz, 2H), 2.97 (m, 2H), 3.91 (s, 3H),4.59 (t, J=6.19 Hz, 1H), 6.47 (d, J=8.84 Hz, 1H), 6.80 (dd, J=8.97, 2.15Hz, 1H), 6.82 (s, 1H), 7.03 (dd, J=6.82, 2.53 Hz, 4H), 7.13 (d, J=9.60Hz, 1H), 7.24 (d, J=8.34 Hz, 2H), 7.29 (m, 6H), 7.40 (d, J=2.02 Hz, 1H)7.58 (d, J=7.58 Hz, 1H), 7.96 (d, J=8.34 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 96% yield. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.96 (m, 2H), 2.28 (s, 3H), 2.74 (m,4H), 2.89 (m, 2H), 2.99 (m,2H), 4.65 (q, J=6.32 Hz, 1H), 6.47 (d, J=8.84 Hz, 1H), 6.80 (dd, J=8.97,2.15 Hz, 1H), 6.82 (s, 1H), 7.03 (m, 4H), 7.14 (d, J=9.60 Hz, 1H), 7.30(m, 8H), 7.40 (d, J=2.02 Hz, 1H), 7.58 (d, J=7.58 Hz, 1H), 8.01 (d,J=8.08 Hz, 2H) HMRS: calcd. for C₄₀H₃₅Cl₂FN₂O₄S, 728.1679; found (ESI+),729.17441. Anal. Calcd for C₄₀H₃₅Cl₂FN₂O₄S: C, 65.84; H, 4.83; N, 3.84.Found: C, 65.49;, H, 5.02; N, 3.72.

EXAMPLE 2644-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-nitrobenzenesulfonyl chlorideaccording to the procedure in Example 1, Step 7 to generate the productin 74% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.97 (m, 2H), 2.73 (q,J=8.08 Hz, 4H), 2.91 (m, 2H), 3.04 (m, 2H), 3.91 (s, 3H), 5.33 (t,J=6.06 Hz, 1H), 6.52 (d, J=8.84 Hz, 1H), 6.80 (dd, J=8.84, 2.02 Hz, 1H),6.90 (s, 1H), 7.06 (dd, J=6.57, 2.53 Hz, 4H), 7.24 (d, J=8.34 Hz, 2H),7.29 (m, 6H), 7.39 (d, J=2.02 Hz, 1H), 7.50 (td, J=7.71, 1.26 Hz, 1H),7.65 (td, J=7.77, 1.39 Hz, 1H), 7.75 (dd, J=7.83, 1.26 Hz, 1H), 7.80(dd, J=7.96, 1.14 Hz, 1H), 7.96 (d, J=8.08 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 100% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.98 (m, 2 H), 2.75 (m, 4H), 2.92 (m, 2H), 3.06 (m, 2H),5.35 (t, J=6.06 Hz, 1H), 6.52 (d, J=8.84 Hz, 1H), 6.81 (dd, J=8.84, 2.02Hz, 1H), 6.91 (s, 1H), 7.07 (dd, J=6.82, 2.53 Hz, 4H), 7.29 (m, 8H),7.40 (d, J=2.02 Hz, 1H), 7.51 (m, 1H), 7.66 (m, 1H), 7.76 (dd, J=7.83,1.26 Hz, 1H), 7.81 (dd, J=7.96, 1.14 Hz, 1H), 8.01 (d, J=8.34 Hz, 2H)HMRS: calcd for C₃₉H₃₄ClN₃O₆S, 707.18568; found (ESI+), 708.19296.

EXAMPLE 2654-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 2-nitrosulfonyl chloride according to the procedure in Example 1,Step 7 in 63% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.99 (m, 2H), 3.19(m, 4H), 3.88 (s, 3H), 4.21 (t, J=6.57 Hz, 2H), 5.40 (t, J=6.19 Hz, 1H),6.57 (d, J=8.84 Hz, 1H), 6.82 (m, 3H), 6.96 (s, 1H), 7.08 (m, 4H), 7.29(m, 6H), 7.49 (td, J=7.71, 1.26 Hz, 1H), 7.52 (d, J=1.77 Hz, 1H), 7.65(td, J=7.71, 1.26 Hz, 1H), 7.80 (m, 2H), 7.93 (d, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 90% yield. 1H NMR (400 MHz, CDCl₃)δ ppm 2.99 (m, 2H), 3.20 (m, 4H), 4.23 (t, J=6.57 Hz, 2H), 5.40 (t,J=6.19 Hz, 1H), 6.57 (d, J=8.84 Hz, 1H), 6.84 (m, 3H), 6.95 (s, 1H),7.08 (m, J=5.68, 3.66 Hz, 4H), 7.29 (m, 6H), 7.50 (m, 2H), 7.65 (td,J=7.77, 1.39 Hz, 1H), 7.80 (m, 2H), 7.98 (d, 2H). HRMS: calcd forC₃₈H₃₂ClN₃O₇S, 709.16495; found (ESI+), 710.17059.

EXAMPLE 2664-[2-(1-benzhydryl-5-chloro-2-{2-[(mesitylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoateand 2-mestitylenesulfonyl chloride according to the procedure in Example1, Step 7 in 89% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.24 (s, 3H), 2.48(s, 6H), 2.90 (m, 2H), 3.05 (m, 2H), 3.16 (t, J=6.69 Hz, 2H), 3.89 (s,3H), 4.17 (t, J=6.69 Hz, 2H), 4.48 (t, J=6.44 Hz, 1H), 6.52 (d, J=8.84Hz, 1H)

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 68% yield. ¹H NMR (400 MHz, CDCl₃)δ ppm 2.24 (s, 3H), 2.48 (s, 6H), 2.90 (q, J=6.99 Hz, 2H), 3.06 (m, 2H),3.17 (t, J=6.69 Hz, 2H), 4.19 (t, J=6.57 Hz, 2H), 4.59 (s, 1H), 6.52 (d,J=8.84 Hz, 1H), 6.82 (m, 6H), 7.02 (m, 4H), 7.29 (m, 6H), 7.52 (d,J=2.02 Hz, 1H), 7.98 (d, J=8.84 Hz, 2H). HRMS: calcd. for C₄₁H₃₉ClN₂O₅S,706.22682; found (ESI+), 707.23370.

EXAMPLE 2674-(3-{1-Benzhydryl-5-chloro-2-[2-(2,4,6-trimethyl-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid

Step 1: To the methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 2-mesitylenebenzenesulfonyl chlorideaccording to the procedure in Example 1, Step 7 to generate the productin 83% yield. ¹H NMR (400 MHz, CHLOROF CDCl₃) δ ppm 1.93 (m, 2H), 2.26(s, 3H), 2.47 (s, 6H), 2.70 (m, 4H), 2.82 (m, 2H), 2.91 (m, 2H), 3.91(s, 3H), 4.36 (t, J=6.44 Hz, 1H), 6.46 (d, J=8.84 Hz, 1H), 6.75 (s, 1H),6.79 (dd, J=8.84, 2.27 Hz, 1H), 6.88 (s, 2H), 7.00 (m, 4H), 7.22 (d,J=8.34 Hz, 2H), 7.28 (m, 6H), 7.39 (d, J=2.02 Hz, 1H), 7.95 (d, J=8.34Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 84% yield. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.94 (m, 2H), 2.26 (s, 3H), 2.47 (s, 6H), 2.71 (m, 4H), 2.83 (m,2H), 2.93 (m, 2H), 4.45 (t, J=5.81 Hz, 1H), 6.46 (d, J=8.84 Hz, 1H),6.75 (s, 1H), 6.79 (dd, J=8.97, 2.15 Hz, 1H), 6.88 (s, 2H), 7.00 (m,4H), 7.27 (m, 8H), 7.40 (d, J=2.02 Hz, 1H), 8.01 (d, J=8.34 Hz, 2H).HMRS: calcd. for C₄₂H₄₁ClN₂O₄S, 704.24756; found (ESI+), 705.25452.

EXAMPLE 2684-(3-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride (1.0 eq.) wastaken up in tetrahydrofuran (0.5 M) and diethyl ether (0.5 M) and cooledto −78° C. nbutyllithium (2.5M, 1.0 eq.) was added dropwise and thereaction stirred for 40 minutes. A volume of sulfur dioxide equal to thevolume of THF was condensed and diluted with two volumes of ether. Thelithium salt of the benzene was canulated into the sulfur dioxide andthe reaction was allowed to slowly warm to room temperature. The solventwas removed and the resulting salt was washed with ether then taken upin hexanes (1.0M) and cooled in and ice bath. Sulfuryl chloride (1.06eq.) was added and the reaction warmed to room temperature and stirredfor 5 hours. The solvent was removed to give2-fluoro-6-trifluoromethylbenznesulfonyl chloride as a white, oily solidin 65% yield. The product was used crude. ¹H NMR (400 MHz, DMSO-D6) □ppm 7.46 (m, 1H), 7.52 (m, 2H).

Step 2: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride accordingto the procedure in Example 1, Step 7 to generate the product in 62%yield. 1H NMR (400 MHz, CDCl₃) □ ppm 1.94 (m, 2H), 2.73 (m, 4H), 2.91(m, 2H), 2.99 (m, 2H), 3.91 (s, 3H), 4.87 (t, J=5.81 Hz, 1H), 6.50 (d,J=8.84 Hz, 1H), 6.81 (dd, J=8.97, 2.15 Hz, 2H), 7.03 (m, 4H), 7.24 (d,J=8.34 Hz, 2H), 7.30 (m, 7H), 7.41 (d, J=2.02 Hz, 1H), 7.62 (m, 2H),7.95 (d, J=8.34 Hz, 2H).

Step 3: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 56% yield. ¹H NMR (400 MHz, CDCl₃)□ ppm 1.96 (m, 2H), 2.75 (m, 4H), 2.92 (m, 2H), 3.00 (m, 2H), 4.93 (t,J=5.94 Hz, 1H), 6.51 (d, J=8.84 Hz, 1H), 6.82 (m, 2H), 7.03 (m, 4H),7.28 (m, 8H), 7.32 (d, J=10.61 Hz, 1H), 7.41 (d, J=2.02 Hz, 1 H,) 7.63(m, 2H), 8.01 (d, J=8.08 Hz, 2H). HRMS calc for [C₄₀H₃₃ClF₄N₂O₄S+H]749.18585 found 749.18578.

EXAMPLE 2694-(2-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2-fluoro-6-trifluoromethylbenzenesulfonyl chloride (Example268, Step 1) according to the procedure in Example 1, Step 7 to affordproduct in 89% yield. ¹ H NMR (400 MHz, CDCl₃) δ ppm 3.00 (m, 2H), 3.12(m, 2H), 3.20 (t, J=6.44 Hz, 2H), 3.88 (s, 3H), 4.20 (t, J=6.44 Hz, 2H),4.99 (t, J=6.06 Hz, 1H), 6.54 (d, J=8.84 Hz, 1H), 6.79 (d, J=8.84 Hz,2H), 6.84 (dd, J=8.97, 2.15 Hz, 1H), 6.88 (s, 1H), 7.04 (dd, J=6.82,2.53 Hz, 4H), 7.28 (m, 6H), 7.33 (m, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.60(m, 2H), 7.93 (d, J=9.10 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 36% yield. ¹H NMR (400 MHz, CDCl₃)□ ppm 3.01 (m, 2H), 3.13 (m, 2H), 3.21 (t, J=6.44 Hz, 2H), 4.22 (t,J=6.44 Hz, 2H), 5.07 (t, J=6.06 Hz, 1H), 6.55 (d, J=8.84 Hz, 1H), 6.83(m, 3H), 6.88 (s, 1H), 7.04 (m, 4H), 7.28 (m, 6H), 7.32 (m, 1H), 7.55(d, J=2.02 Hz, 1H), 7.61 (m, 2H), 7.98 (d, J=8.84 mHz, 2H). HRMS calcfor [C₃₉H₃₁ClF₄N₂O₅S+H] 751.16511 found 751.16431.

EXAMPLE 2704-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: 2,6-Dimethylbenzenesulfonyl chloride was prepared from2-bromo-1,3-dimethylbenzene according to the procedure in Example 18,Step 1-2. The reaction gave product as a white solid in 84% yield. ¹HNMR (400 MHz, DMSO-D6) □ ppm 2.54 (s, 6H), 6.94 (d, J=7.33 Hz, 2H), 7.02(m, 1H).

Step 2: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2,6-dimethylbenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 66% yield. ¹HNMR (400 MHz, CDCl₃) □ ppm 1.93 (m, 2H), 2.50 (s, 6H), 2.70 (m, 4H),2.82 (m, 2H), 2.93 (m, 2H), 3.91 (s, 3H), 4.40 (t, J=6.32 Hz, 1H), 6.47(d, J=8.84 Hz, 1H), 6.77 (s 1H), 6.80 (dd, J=8.97, 2.15 Hz, 1H), 7.00(m, 4H), 7.07 (d, J=7.58 Hz, 2H), 7.22 (d, J=8.08 Hz, 2H), 7.27 (m, 7H),7.40 (d, J=2.02 Hz, 1H), 7.95 (d, J=8.08 Hz, 2H).

Step 3: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 96% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.81 (m, 2 H,) 2.50 (s, 6H), 2.65 (m, 4H), 2.81 (m, 2H),2.87 (m, 2H), 6.45 (d, J=8.84 Hz, 1H), 6.77 (dd, J=8.84, 2.27 Hz, 1H),6.94 (s, 1H), 7.02 (m, 4H), 7.17 (d, J=7.58 Hz, 2H), 7.28 (d, J=8.34 Hz,2H), 7.33 (m, 6H), 7.43 (d, J=2.27 Hz, 1H), 7.70 (t, J=5.81 Hz, 1H),7.85 (d, J=8.08 Hz, 2H). HRMS calc for [C₄₁H₃₉ClN₂O₄S+H] 691.23919 found691.23872.

EXAMPLE 2714-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2,6-dimethylbenzenesulfonyl chloride (Example 270, Step 1)according to the procedure in Example 1, Step 7 to afford product in 88%yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 2.51 (s, 6H), 2.90 (m, 2H), 3.06(m, 2H), 3.16 (t, J=6.69 Hz, 2H), 3.89 (s, 3H), 4.17 (t, J=6.57 Hz, 2H),4.50 (t, J=6.19 Hz, 1H), 6.53 (d, J=8.84 Hz, 1H), 6.79 (d, J=9.10 Hz,2H), 6.83 (m, 2H), 7.02 (m, 4H), 7.06 (d, J=7.58 Hz, 2H), 7.23 (m, 1H),7.28 (m, 6H), 7.53 (d, J=2.02 Hz, 1H), 7.93 (d, J=8.84 Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 79% yield. ¹H NMR (400 MHz,DMSO-D7) □ ppm 2.48 (s, 6H), 2.85 (m, 2H), 2.95 (m, 2H),3.08 (t, J=6.57Hz, 2H), 4.15 (t, J=6.69 Hz, 2H), 6.48 (d, J=8.84 Hz, 1H), 6.79 (dd,J=8.84, 1.77 Hz, 1H), 6.90 (d, J=8.84 Hz, 2H), 6.95 (s, 1H), 7.01 (m,4H), 7.14 (d, J=7.58 Hz, 2H), 7.29 (m, 6H), 7.63 (d, J=2.02 Hz, 1H),7.73 (t, J=5.94 Hz, 1H), 7.82 (d, J=8.84 Hz, 2H). HRMS calc for[C₄₀H₃₇ClN₂O₅S+H] 693.21845 found 693.21791.

EXAMPLE 2724-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: 2,6-Diethylbenzenesulfonyl chloride was prepared from2-bromo-1,3-diethylbenzne according to the procedure in Example 18, Step1-2. The reaction gave product as a pale yellow, oily solid in 36%yield. ¹H NMR (400 MHz, DMSO-D6) □ ppm 1.13 (t, J=7.33 Hz, 6H), 3.08 (q,J=7.33 Hz, 4H), 6.96 (d, J=7.58 Hz, 2H), 7.10 (m, 1H).

Step 2: To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2,6-diethylbenzenesulfonyl chloride according to the procedurein Example 1, Step 7 to afford product in 72% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.10 (t, J=7.33 Hz, 6H), 2.91 (m, 6H), 2.99 (m, 2H), 3.11(t, J=6.69 Hz, 2H), 3.81 (s, 3H), 4.18 (t, J=6.69 Hz, 2H), 6.49 (d,J=8.84 Hz, 1H), 6.80 (dd, J=8.84, 2.02 Hz, 1H), 6.93 (d, J=8.84 Hz, 2H),6.97 (s, 1H), 7.02 (m, 4H), 7.17 (d, J=7.58 Hz, 2H), 7.32 (m, 5H), 7.38(t, J=7.71 Hz, 1H), 7.65 (d, J=2.02 Hz, 1H), 7.74 (t, J=5.94 Hz, 1H),7.85 (d, J=8.84 Hz, 2H).

Step 3: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 88% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.10 (t, J=7.33 Hz, 6H), 2.91 (m, 6H), 2.98 (d, J=7.83Hz, 2H), 3.10 (t, J=6.57 Hz, 2H), 4.17 (t, J=6.69 Hz, 2H), 6.49 (d,J=8.84 Hz, 1H), 6.80 (dd, J=8.84, 2.02 Hz, 1H), 6.91 (d, J=9.09 Hz, 2H),6.97 (s, 1H), 7.02 (m, 4H), 7.17 (d, J=7.58 Hz, 2H), 7.32 (m, 5H), 7.38(t, J=7.58 Hz, 1H), 7.65 (d, J=2.27 Hz, 1H), 7.74 (t, J=5.81 Hz, 1H),7.83 (d, J=8.84 Hz, 2H). HRMS calc for [C₄₂H₄₁ClN₂O₅S+H] 721.24975 found721.24876.

EXAMPLE 2734-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2,6-diethylbenzenesulfonyl chloride (Example 272, Step 1)according to the procedure in Example 1, Step 7 to generate the productin 71% yield. ¹H NMR (400 MHz, DMSO-D6) □ ppm 1.11 (t, J=7.33 Hz, 6H),1.81 (m, 2H), 2.65 (m, 4H), 2.84 (m, 2H), 2.90 (m, 6H), 3.84 (s, 3H),6.44 (d, J=8.84 Hz, 1H), 6.77 (dd, J=8.84, 2.02 Hz, 1H), 6.94 (s, 1H),7.02 (m, 4H), 7.19 (d, J=7.58 Hz, 2H), 7.33 (m, 7H), 7.40 (t, J=7.71 Hz,1H), 7.43 (d, J=2.02 Hz, 1H), 7.70 (t, J=5.68 Hz, 1H), 7.86 (d, J=8.34Hz, 2H).

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 85% yield. ¹H NMR (400 MHz,DMSO-D6) □ ppm 1.11 (t, J=7.33 Hz, 6H), 1.81 (m, 2H), 2.65 (m, 4H), 2.84(m, 2H), 2.91 (m, 6H), 6.45 (d, J=8.84 Hz, 1H), 6.77 (dd, J=8.84, 2.02Hz, 1H), 6.95 (s, 1H), 7.02 (m, 4H),7.19 (d, J=7.58 Hz, 2H), 7.28 (d,J=8.34 Hz, 2H), 7.33 (m, 5H), 7.40 (m, 1H), 7.43 (d, J=2.27 Hz, 1H),7.70 (t, J=5.68 Hz, 1H), 7.84 (d, J=8.34 Hz, 2H). HRMS calc for[C₄₃H₄₃ClN₂O₄S+H] 719.27049 found 719.27028.

EXAMPLE 2744-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: 1,3-dimethoxybenzene (1.0 eq). was taken up in diethy ether(0.2M) and n-butyllithium (1.0 eq.) was added dropwise. The reaction washeated to reflux for three hours. It was cooled to room temperature thenit was placed in a dry ice acetone bath and cooled to −50° C. Bromide(0.98 eq.) was added and the reaction was allowed to warm slowly to roomtemperature. The reaction was quenched with saturated sodium thiosulfateand the aqueous layer was extracted with ether. The organic extractswere washed with brine, dried over sodium sulfate and concetrated togive a brown solid. The solid was recrystalized from hexanes to give theproduct as a white solid in 27% yield. ¹H NMR (400 MHz, DMSO-D6) □ ppm3.83 (s, 6H), 6.73 (d, J=8.34 Hz, 2H), 7.30 (t, J=8.34 Hz, 1H).

Step 2: 2,6-Dimethoxybenzenesulfonyl chloride was prepared from2-bromo-1,3-dimethoxybenzne according to the procedure in Example 1,Step 1. The reaction gave a mixture of sulfonyl chloride and anotherproduct as a white solid.

Step 3. To methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoatewas added 2,6-dimethoxybenzenesulfonyl chloride according to theprocedure in Example 1, Step 7 to afford product in 72% yield. 1H NMR(400 MHz, CDCl₃) □ ppm 3.08 (m, 2H), 3.14 (m, 2H), 3.20 (t, J=6.69 Hz,2H), 3.64 (s, 6H), 3.88 (s, 3H), 4.18 (t, J=6.69 Hz, 2H), 5.41 (t,J=5.68 Hz, 1H), 6.42 (d, J=8.84 Hz, 1H), 6.52 (d, J=8.59 Hz, 2H), 6.79(m, 3H), 6.91 (s, 1H), 7.02 (m, 4H), 7.25 (m, 6H), 7.36 (t, J=8.46 Hz, 1H, 7.54 (d, J=2.02 Hz, 1H), 7.93 (d, J=8.84 Hz, 2H). m/z (M−) 737.

Step 4. The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 100% yield. 1H NMR (400 MHz,CDCl₃) □ ppm 3.08 (m, 2H), 3.15 (m, 2H), 3.21 (t, J=6.69 Hz, 2H), 3.64(s, 6H), 4.20 (t, J=6.57 Hz, 2H), 5.44 (m, 1H), 6.42 (d, J=8.84 Hz, 1H),6.53 (d, J=8.59 Hz, 2H), 6.79 (dd, J =8.84, 2.02 Hz, 1H), 6.83 (d,J=8.84 Hz, 2H), 6.91 (s, 1H), 7.02 (m, 4H), 7.25 (m, 6H),7.36 (t, J=8.46Hz, 1H), 7.54 (d, J=2.02 Hz, 1H), 7.98 (d, J=8.84 Hz, 2H). HRMS calc for[C₄₀H₃₇ClN₂O₇S+H] 725.20729 found 719.27028.

EXAMPLE 2754-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoatewas added 2,6-dimethoxybenzenesulfonyl chloride(Example 274, Step 1)according to the procedure in Example 1, Step 7 to generate the productin 80% yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 1.94 (m, 2H), 2.72 (m, 4H),3.01 (m, 4H), 3.59 (s, 6H), 3.91 (s, 3H), 5.37 (m, 1H), 6.37 (d, J=8.84Hz, 1H), 6.53 (d, J=8.59 Hz, 2H), 6.76 (dd, J=8.97, 2.15 Hz, 1H), 6.84(s, 1H), 6.98 (m, 4H), 7.21 (d, J=8.34 Hz, 2H), 7.26 (m, 6H), 7.38 (m,2H), 7.94 (d, J=8.34 Hz, 2H). m/z (M+737.

Step 2: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 91% yield. ¹H NMR (400 MHz, CDCl₃)□ ppm 1.95 (m, 2H), 2.74 (m, 4H), 3.02 (m, 4H), 3.60 (s, 6H), 5.41 (s,1H), 6.37 (d, J=8.84 Hz, 1H), 6.53 (d, J=8.59 Hz, 2H), 6.76 (dd, J=8.84,2.27 Hz, 1H), 6.84 (s, 1H), 6.99 (m, 4H), 7.25 (m, 8H), 7.37 (t, J=8.46Hz, 1H), 7.40 (d, J=2.02 Hz, 1H), 7.99 (d, J=8.34 Hz, 2H). HRMS calc for[C₄₁H₃₉ClN₂O₆S+H] 723.22902 found 723.22893.

EXAMPLE 2764-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-nitro-1H-indol-3-yl)ethoxy]benzoicacid

Step 1. 4-Nitroaniline (1.0 eq.) was taken up in water (0.8 M) andconcetrated HCl (10.8 M). Iodine monochloride (1 eq.) was added to a 4to 1 solution of water and concetrated HCl (1.3 M) and cooled to 0° C.The ICl solution was added to the aniline solution and the reaction satat room temperature for 20 hours. The reaction was filtered to give theiodinated product as a yellow solid in 97.3% yield. ¹H NMR (300 MHz,DMSO-D6) δ ppm 6.75 (d, J=9.07 Hz, 1H), 7.98 (dd, J=9.07, 2.47 Hz, 1H),8.40 (d, J=2.47 Hz, 1H). MS m/z 263 (M−H).

Step 2. To the 2-iodo-4-nitroaniline (1 eq.) and benzhydrylbromide (1.3eq were taken up in dichloroethane (0.8 M). Diisopropylethylamine (1.1eq.) was added and the reaction heated to 50° C. for 20 hours. Thereaction mixture was cooled and washed with 1 N HCl, dried over Na₂SO₄and concentrated. Purifiction using flash chromatography (10% ethylacetate in hexanes) gave the alkylated product in 81% yield. ¹H NMR (400MHz, CDCl₃) δ ppm 5.56 (d, J=4.80 Hz, 1H), 5.67 (d, J=5.05 Hz, 1H), 6.36(d, J=9.10 Hz, 1H), 7.32 (m, 6H), 7.38 (m, 4H), 7.99 (dd, J=9.09, 2.53Hz, 1H) 8.61 (d, J=2.53 Hz, 1H).

Step 3. Benzhydryl-(4-nitro-2-iodo-phenyl)-amine (1 eq.),4-(6-hydroxy-hex-3-ynyloxy)-benzoic acid methyl ester (1.5 eq.), LiCl (1eq.) KOAc (5 eq.) and palladium (II) acetate (0.04 eq.) were added to aroundbottom containing 10 mL of DMF that had been degassed with argon.The reaction heated to 100° C. 7.5 hours. It was then cooled, dilutedwith ethyl acetate, washed with water and brine, dried over Na₂SO₄ andconcentrated to give a brown solid. Purification by flash chromatographygave two products,4-{2-[1-benzhydryl-5-nitro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester and the desired,4-{2-[1-benzhydryl-5-nitro-3-(2-hydroxy-ethyl)-1H-indol-2-yl]-ethoxy}-benzoicacid methyl ester in an overall yield of 71%. The products were notseperable by flash chromatography and were both carried on to the nextstep. ¹H NMR (400 MHz, CDCl₃) □ ppm 1.66 (t, J=5.56 Hz, 1H), 1.80 (t,J=5.18 Hz, 1H), 3.14 (m, 4H), 3.35 (m, 4H), 3.81 (m, 2H), 3.87 (m,J=1.52 Hz, 6H), 3.97 (q, J=6.32 Hz, 2H), 4.10 (t, J=6.82 Hz, 2H), 4.31(t, J=6.19 Hz, 2H), 6.58 (d, J=4.04 Hz, 1H), 6.60 (d, J=4.04 Hz, 1H),6.67 (d, J=9.10 Hz, 2H), 6.89 (d, J=8.84 Hz, 2H), 7.10 (m, 9H), 7.20 (s,1H), 7.32 (m, 12H), 7.75 (m, 2H), 7.90 (d, J=8.84 Hz, 2H), 7.95 (d,J=9.09 Hz, 2H), 8.52 (d, J=2.27 Hz, 1H), 8.59 (d, J=2.27 Hz, 1H).

Step 4. The regiosiomers(1.0 eq.) from the previous step were taken upin THF. Triethylamine (1.2 eq.) and methanesulfonyl chloride (1.2 eq.)were added. The reaction stirred until the starting material wasconsumed as monitored but TLC. The reaction was diluted withdichloromethane and washed with water and brine. It was dried overNa₂SO₄ and concentrated. The reaction gave an inseperable mixture ofisomers in 100% yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 2.81 (s, 3H), 2.90(s, 3H), 3.35 (m, 8H), 3.87 (m, J=1.52 Hz, 6H), 4.07 (t, J=6.19 Hz, 2H),4.14 (t, J=7.20 Hz, 2H), 4.30 (t, J=6.06 Hz, 2H), 4.49 (t, J=6.69 Hz,2H), 6.62 (d, J=6.57 Hz, 1H), 6.65 (d, J=6.57 Hz, 1H), 6.69 (d, J=8.84Hz, 2H), 6.88 (d, J=9.09 Hz, 2H), 7.02 (s, 1H), 7.10 (dd, J=7.71, 4.67Hz, 8H), 7.23 (s, 1H), 7.34 (m, 12H), 7.79 (m, 2H), 7.91 (d, J=8.84 Hz,2H), 7.96 (d, J=8.84 Hz, 2H), 8.49 (d, J=2.27 Hz, 1H), 8.62 (d, J=2.02Hz, 1H).

Step 5. The mixture of crude mesylates (1 eq.) from above and sodiumazide (2.2 eq.) were taken up in DMSO (0.05 M). The reaction stirred atroom temperature until the starting material was consumed as moniteredby TLC. The reaction was diluted with ethyl acetate, washed with waterand brine, dried over Na₂SO₄ and concentrated to give the desired azidesin quantitative yield. ¹H NMR (400 MHz, CDCl₃) □ ppm 3.12 (m, 4H), 3.33(m, 6H), 3.64 (t, J=6.82 Hz, 2H), 3.88 (m, J=1.52 Hz, 6H), 4.05 (t,J=6.32 Hz, 2H), 4.29 (t, J=6.19 Hz, 2H), 6.65 (m, 4H), 6.87 (d, J=8.84Hz, 2H), 7.02 (s, 1H), 7.10 (m, 8H), 7.21 (s, 1H), 7.34 (m, 12H), 7.78(m, 2H), 7.91 (d, J=8.84 Hz, 2H), 7.96 (d, J=8.84 Hz, 2H), 8.49 (d,J=2.27 Hz, 1H), 8.61 (d, J=2.27 Hz, 1H).

Step 6. The mixture of inseperable azides (1.0 eq.) from Step 5 andtriphenylphosphine (1.1 eq.) were taken up in THF and stirred at roomtemperature until the starting material was consumed giving a productwith a higher Rf by TLC. 1 ml of water was added to the reaction and itcontinued to stir at room temperature until TLC showed the disapperanceof the higher Rf intermediate. The THF was removed in vacuo and theresulting solid was taken up in ethyl acetate, washed with water andbrine, dried over Na₂SO₄ and concentrated. Purification by flashchromatography gave 43% overall yield of reduced products. Theregioisomers where separated using flash chromatography (gradientelution 0.25% methanol in dichloromethane to 10% methanol indichloromethane.) The regioisomers were identified by NMR and thedesired compound,4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester, was taken on to the next step. 1H NMR (400 MHz,CDCl₃) δ ppm 3.30 (m, 6H), 3.88 (s, 3H), 4.27 (t, J=6.57 Hz, 2H), 6.56(d, J=9.35 Hz, 1H), 6.88 (d, J=9.10 Hz, 2H), 7.10 (dd, J=6.44, 2.65 Hz,4H), 7.32 (m, 7H), 7.72 (dd, J=9.09, 2.27 Hz, 1H), 7.95 (d, J=8.84 Hz,2H), 8.60 (d, J=2.27 Hz, 1H). MS m/z 550 (M+).

Step 7. To4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-nitro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was added α-toluenesulfonyl chloride according to theprocedure in Example 1, Step 7 to generate the product in 61% yield. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.89 (m, 2H) 3.09 (m, 2H), 3.25 (t, J=6.06Hz, 2H), 3.88 (s, 3H), 4.09 (s, 2H), 4.15 (m, 1H), 4.25 (t, J=6.06 Hz,2H), 6.61 (d, J=9.35 Hz, 1H), 6.84 (d, J=8.84 Hz, 2H), 6.97 (s, 1H),7.07 (m, 4H),7.20 (m, J=8.08, 1.52 Hz, 2H),7.32 (m, 9H), 7.77 (dd,J=9.10, 2.27 Hz, 1H), 7.95 (d, J=9.10 Hz, 2H), 8.59 (d, J=2.27 Hz, 1H).MS m/z 703 (M−H).

Step 8: The ester intermediate was hydrolyzed according to Step 8,Example 1 to afford the title acid in 75% yield. ¹H NMR (400 MHz, CDCl₃)δ ppm 2.90 (m, 2H), 3.10 (m, 2H), 3.26 (t, J=6.06 Hz, 2H), 4.10 (s, 2H),4.26 (t, J=6.06 Hz, 2H), 4.37 (t, J=6.19 Hz, 1H), 6.61 (d, J=9.35 Hz,1H), 6.85 (d, J=9.09 Hz, 2H), 6.97 (s, 1H), 7.07 (m, 4H), 7.20 (m, 2H),7.32 (m, 9H), 7.76 (dd, J=9.10, 2.27 Hz, 1H), 7.97 (d, J=8.84 Hz, 2H),8.58 (d, J=2.27 Hz, 1H). HRMS: calcd. for C₃₉H₃₅N₃O₇S, 689.2196; found(ESI+) 690.22581.

EXAMPLE 2774-(3-{1-Benzhydryl-5-chloro-2-[2-({[2-(2-chloro-1-methylethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and2-(2-chloro-1-methylethyl)benzenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 65% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. HRMS calc for[C₄₂H₄₀Cl₂N₂O₄S+H] 739.21586 found 739.21611.

EXAMPLE 2784-(2-{1-benzhydryl-5-chloro-2-[2-({[2-chloro-1-methylethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2-(2-chloro-1-methylethyl)benzenesulfonylchloride according to the procedure in Example 1 Step 7 in 61% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. m/z (M−1)=739.3

EXAMPLE 2794-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 2,6-dimethylbenzylsulfonyl chloride according tothe procedure in Example 1 Step 7 in 45% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield. m/z (M−1)=738.2

EXAMPLE 2804-[3-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]-ethyl}-1H-indol-3-yl)propyl]benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) and cyclopropanesulfonyl chloride according to theprocedure in Example 1 Step 7 in 83% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 80% yield. HRMS calc forC₃₆H₃₅ClN₂O₄S, 626.2006; found (ESI+), 627.20734.

EXAMPLE 2814-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added and 2-phenylethanesulfonyl chloride(prepared following a procedure in J. Org. Chem. 1984, 49, 5124-5131)according to the procedure in Example 1 Step 7 to generate the productin 77% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 82% yield. HRMS calc forC₄₁H₃₉ClN₂O₄S, 690.2313; found (ESI+), 691.2383.

EXAMPLE 2824-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 42) and 2-phenylethanesulfonyl chloride according tothe procedure in Example 1 Step 7 in 81% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 85% yield. HRMS calcd forC₄₀H₃₇ClN₂O₅S, 692.2115; found (ESI+), 693.2185.

EXAMPLE 283 3-(2-(1-Benzhydryl-5-chloro-2-(2-phenylmethylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid

Step 1: Crude2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanolfrom step 6, example 142 was treated with 3-Hydroxy-benzoic acid methylester according to the procedure in Example 142 step 8 to yield thedesired3-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 85% yield.

Step 2: The deprotected compound was prepared according to the proceduredescribed for Example 142 step 9. The crude3-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was used in the next step directly without furtherpurification.

Step 3-5:3-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was prepared according to the procedure described forexample 146 steps 3-7 in 57% (3 steps).

Step 6: To3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was added □-toluenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 73% yield.

Step 7: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 88% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S+H] 679.2028 found 679.2029.

EXAMPLE 2843-(2-(1-benzhydryl-5-chloro-2-(2-((3,4-dichlorophenyl)methylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid

Step 1: To3-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester (Step 5, Example 279) was added3,4-dichlorophenylmethanesulfonyl chloride according to the procedure inExample 1 Step 7 to generate the product in 84% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 91% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+H] 747.12486 found 747.12423.

EXAMPLE 2852-(2-(1-benzhydryl-5-chloro-2-(2-(phenylmethylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoicacid

Step 1: Crude2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanolfrom step 6, example 142 was treated with 2-Hydroxy-benzoic acid methylester according to the procedure in Example 142 step 8 to yield thedesired2-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoicacid methyl ester in 60% yield.

Step 2: The deprotected compound was prepared according to the proceduredescribed for Example 142 step 9. The crude2-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was used in the next step directly without furtherpurification.

Step 3-5:2-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoicacid methyl ester was prepared according to the procedure described forexample 146 steps 3-7 in 60% (3 steps).

Step 6: To2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy)-benzoicacid methyl esterwas added α-toluenesulfonyl chloride according to theprocedure in Example 1 Step 7 to generate the product in 90% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS calc for[C₃₉H₃₅ClN₂O₅S+H] 679.2028 found 679.20358.

EXAMPLE 2862-(2-(1-benzhydryl-5-chloro-2-(2-((3,4-dichlorophenyl)methylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid

Step 1: To2-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy)-benzoicacid methyl ester (Step 5, Example 281) was added3,4-dichlorophenylmethanesulfonyl chloride according to the procedure inExample 1 Step 7 to generate the product in 84% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 89% yield. HRMS calc for[C₃₉H₃₃Cl₃N₂O₅S+H] 747.12486 found 747.12457.

EXAMPLE 2874-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step 1, was added 2,4-dichlorothiophenol according to theprocedure in Example 81 step 2. The crude was purified by thepreperative HPLC in 50% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 776.92.

EXAMPLE 2884-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-difluorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: To methyl4-{2-[1-benzhydryl-5-chloro-2-(2-chloromethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoate,Example 81 step 1, was added 2,4-difluorothiophenol according to theprocedure in Example 81 step 2. The crude was purified by thepreperative HPLC in 27% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 100% yield. m/z (M−1) 744.97.

EXAMPLE 2894-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)sulfinyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid

Step 1: The methyl4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoate(Step 1 Example 220) in THF was oxidized with mCPBA (1.1 equiv.) Thecrude was purified by the flash column with 30% EtOAc/hexane in 42%yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 93% yield. m/z (M−1) 795.14.

EXAMPLE 2904-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-hydroxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: Methyl4-(2-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoate (0.55 g, 0.70 mmol), (Step 1,Example 184) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) washydrogenated. The resulting mixture was filtered through Celite andconcentrated. The residue was chromatographed with 35-40% EtOAC/hexaneto give the desired product (0.50 g, 95%).

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 90% yield. HRMS: calcd forC₃₈H₃₃ClN₂O₆S, 680.1748; found (ESI+), 681.18118

EXAMPLE 291N-{2-[1-benzhydryl-5-chloro-3-(2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}ethyl)-1H-indol-2-yl]ethyl}-1-(3,4-dichlorophenyl)methanesulfonamide

Step 1: The2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142) was coupled with 4-Hydroxy-benzaldehyde accordingto the conditions described in Example 189, Step 1 to yield4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-benzaldehydein 70% yield.

Step 2: The silyl ether from above was deprotected following the Example142, step 9 to yield4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1#H!-indol-3-yl]-ethoxy}-benzaldehydein 90% yield.

Step 3: The alcohol from above was activated by conversion to themesylate as described in Step 10 Example 142 to yield the desiredmesylate which was used without purification in the next step.

Step 4: The mesylate from above was treated under the conditionsdescribed in Step 11 Example 142 to generate4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehydein 98% yield (2 steps).

Step 5: The mixture of4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzaldehyde(1.29 g, 2.41 mmole, 1.0 equiv.), 2,4-thiazolidine dione (0.41 g, 3.13mmole, 1.3 equiv.) and piperidine (0.12 ml, 1.21 mmole, 0.5 equiv.) inEtOH (125 ml) was refluxed overnight. EtOH was removed on vacuo. Theresidue was diluted in EtOAc and washed with water, then brine. Theorganic layer was dried over MgSO₄ and concentrated, and the residue waschromatographed with 30-35% EtOAc/hexane to obtain5-(4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzylidene)-thiazolidine-2,4-dione(1.33 g, 87%).

Step 6: To a solution of the product from step 5 in THF (80 ml) wasadded Ph₃P in small portions. The mixture was stirred for 1 day. 3 ml ofwater was added, and stirred for an additional 2 days. The producedsolid, which was identified as triphenyl phosphine imine of the aboveazide.(60%) by LC/MS, was filtered.

Step 7: The imine (250 mg, 0.29 mmole, 1.0 equiv.) from step 6, and(3,4-dichlorophenyl)methylsulfonyl chloride in CH₂Cl₂ (10 ml) andsaturated NaHCO₃ (5 ml) was stirred overnight according to the procedurein Example 1 Step 7 to generate the product in 7% yield. m/z (M−1)830.45

EXAMPLE 292N-[2-(1-Benzhydryl-5-chloro-3-{2-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-ethyl}-1H-indol-2-yl)-ethyl]-2-methyl-benzenesulfonamide

Step 1: The mixture of triphenylphosphine imine (300 mg, 0.35 mmole, 1.0equiv.) from Step 6, Example 291 and 2-methyl-benzenesulfonyl chloridein CH₂Cl₂ (15 ml) and saturated NaHCO₃ (5 ml) was stirred overnightaccording to the procedure in Example 1 Step 7 to generate the productin 3% yield. HRMS calc for [C₄₂H₃₆ClN₃O₅S −H] 760.1723 found 760.1728.

EXAMPLE 2934-{3-[1-Benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: To the methyl4-{3-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoate(Step 6, Example 42) was added 1-Methyl-1H-imidazole-2-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 to generate the productin 70% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 92% yield. HRMS calc for[C₃₇H₃₅ClN₄O₄S+H] 667.2141 found 667.2137.

EXAMPLE 2944-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid

Step 1: This compound was prepared from methyl4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate(Step 6, Example 1) and 1-Methyl-1H-imidazole-2-sulfonyl chlorideaccording to the procedure in Example 1 Step 7 in 76% yield.

Step 2: The ester intermediate was hydrolyzed according to Step 8Example 1 to afford the title acid in 87% yield. HRMS calc for[C₃₆H.₃₃ClN₄O₅.S+H] 669.1933 found 669.1933.

EXAMPLE 2954-{3-[1-benzhydryl-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid

Step 1: A mixture of methyl-4-iodobenzoate (5.3 g, 20.2 mmol), allylalcohol (1.78 g, 30.3 mmol), NaHCO₃ (4.24 g, 50.5 mmol), Pd(OAc)₂ (0.14g, 0.60 mmol), (n-Bu)₄NBr (6.55 g, 20.2 mmol) and 4-A molecular Sieves(4.1 g) in anhydrous DMF (69 mL) was stirred at room temperature for 4days. The reaction mixture was filtered through celite and the filtratepoured onto water and extracted with EtOAc. Organic layer was washedwith brine, dried (Na₂SO₄), and concentrated under vacuum. Flashchromatography (silica gel, 10-20% EtOAc-hexanes) gave 2.11 g (85% basedon the recovered starting material) of the desired4-(3-Oxo-propyl)-benzoic acid methyl ester as a clear oil.

Step 2: To a solution of 2-Methyl-1H-indole (0.86 g, 5.2 mmol) and4-(3-Oxo-propyl)-benzoic acid methyl ester (1.0 g, 5.2 mmol) inmethylene chloride (50 mL), was added TFA (1.78 g, 15.6 mmol), followedby triethylsilane (1.81 g, 15.6 mmol). The reaction mixture was stirredovernight, quenched with sat. NaHCO₃ solution (50 mL), and the organiclayer was washed with sat. NaHCO₃ solution, water, brine, and dried(Na₂SO₄). Solvent was removed under reduced pressure, and the residuewas purified by flash column chromatography with 10-20% EtOAc/hexanes toyield the desired 4-[3-(2-Methyl-1H-indol-3-yl)-propyl]-benzoic acidmethyl ester in 88% (1.67 g) yield.

Step 3: To a solution of the product from step 2 (1.66 g, 4.86 mmol) inDMF (20 mL) was added NaH (60% in mineral oil, 0.24 g, 5.83 mmol) underN₂ atmosphere. The mixture was stirred for 1 h at room temperature,followed by the dropwise addition of benzhydryl bromide (1.8 g, 7.29mmol) in DMF (5 mL). This reaction mixture was stirred overnight at roomtemperature. Water (500 mL) was added to reaction mixture, it wasextracted with EtOAc, washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure to a brown syrup, which was purifiedby silica-gel chromatography using 10% EtOAc/hexanes as eluent toisolate 4-[3-(1-Benzhydryl-2-methyl-1H-indol-3-yl)-propyl]-benzoic acidmethyl ester as a white solid in 76% (1.47 g) yield.

Step 4: The product from above (1.46 g, 2.87 mmol) was dissolved in CCl₄(14.5 mL), followed by the addition of NBS (1.02 g, 5.73 mmol) andbenzoyl peroxide (2 mg). The reaction mixture was heated to reflux for 1h (until all the starting material disappeared). This mixture was cooledto room temperature, filtered and the solid was washed with CCl₄. Thefiltrate was evaporated to a brown residue, which was dissolved inacetone (40 mL) and water (4 mL), Ag₂CO₃ (1.75 g, 3.16 mmol) was thenadded to this solution and after being stirred overnight at roomtemperature, it was filtered through celite, the solvent was evaporatedunder reduced pressure, and water was added to the residue. It wasextracted with EtOAc, washed with brine, dried (Na₂SO₄), and evaporatedto a syrup, which was purified by 10% EtOAc/hexanes to isolate the4-[3-(1-Benzhydryl-2-formyl-1H-indol-3-yl)-propyl]-benzoic acid methylester (1.13 g) in 85% yield. Alternatively the dibromide from thereaction with NBS could be poured into DMSO (10-20% concentration byweight) and stirred for 30 minutes at room temperature. When thereaction was deemed complete it was poured into water and the resultingprecipitate was isolated by filtration, the cake was washed with waterand dried to yield an essentially quantitative yield.

Step 5: To a solution of the indole from above (0.52 g, 1 mmol) inCH₃NO₂ (6.2 mL) was added NH₄OAC (0.077 g, 1 mmol), the mixture washeated to reflux for 1 h, NH₄OAc (0.077 g, 1 mmol) was then added,heating at reflux was continued for an additional 1 h, NH₄OAc (0.077 g,1mmol) was added again and the heating continued for further 1 h. Thereaction mixture was allowed to attain room temperature, EtOAc (50 mL)was added, followed by the addition of 1 00 mL water. The aqueous layerwas extracted with EtOAc, and the combined organic layers were washedwith brine, dried (Na₂SO₄), and evaporated to a yellow foam, which wassubjected to chromatographic purification using 10% EtOAc/hexanes as aneluent to yield4-{3-[1-Benzhydryl-2-(2-nitro-vinyl)-1H-indol-3-yl]-propyl}-benzoic acidmethyl ester as a yellow foam in 75% yield (0.38 g).

Step 6: Zn(Hg) was made by adding HgCl₂ (3.4 g, 7.2 mmol) to a mixtureof Zn-dust (34.68 g, 530.35 mmol) and 5% HCl (38 mL) in a 100 mL beaker,this mixture was stirred vigorously for 10 min. Aqueous phase wasdecanted and added 38 mL of 5% HCl again and the mixture was stirred for10 min. Aqueous phase was decanted. This solid was added to the vinylnitro compound 6 (15 g, 26.57 mmol) in THF (660 mL) and conc. HCl (64.5mL). This mixture was stirred at room temperature for 1 h, then atreflux for 15 min. The reaction mixture was cooled to room temperatureand filtered through celite. Aq. NH₄OH solution (200 mL) was added tothe filtrate, stirred for 15 min and THF was removed under reducedpressure. The aqueous layer was extracted with CH₂Cl₂, combined organiclayer was washed with brine, dried (Na2SO4) and concentrated to a brownfoam, which was purified by column chromatography by eluting the columnwith CHCl₃ in the beginning to remove non-polar impurities then with 2%MeOH/CHCl₃ to isolate the desired4-{3-[2-(2-Amino-ethyl)-1-benzhydryl-1H-indol-3-yl]-propyl)-benzoic acidmethyl ester in 40% yield (6.1 g)

Step 7: To the amine(1.0 equiv.) and sat. NaHCO₃ (0.14 M) in CH₂Cl₂(0.07 M) was added 2-Chloro-benzenesulfonyl chloride (1.0 equiv.). After1 h the mixture was poured into saturated sodium bicarbonate andextracted with CH₂Cl₂. The combined organic phase was washed with brine,dried over sodium sulfate and purified by column chromatography toafford 92% of the desired4-(3-{1-Benzhydryl-2-[2-(2-chloro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid methyl ester.

Step 8: The resulting ester was hydrolyzed by stirring with 1 N NaOH (5equiv.) in THF (0.07 M) and enough MeOH to produce a clear solution. Thereaction was monitored by TLC (10% MeOH—CH₂Cl₂) for the disappearance ofstarting material. The mixture was stirred overnight at room temperatureand then. concentrated, diluted with H₂O, and acidified to pH 2-4 using1 M HCl. The aqueous phase was extracted with EtOAc and the organicphase was washed with brine, dried over sodium sulfate, and concentratedto afford the title compound in 56% yield. m/z (M−1) 663.2

EXAMPLE 2964-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid

Step 1: [(3,4-dichlorophenyl)methyl]sulfonyl chloride (0.07 g, 0.24mmol) was added to a mixture of ethyl4-{2-[2-(2-Aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}-2-fluoro-benzoate(Step 6, Example 190, 0.17 g, 0.2 mmol) and K₂CO₃ (0.055 g, 0.4 mmol) inCH₂Cl₂ (2 mL) and water (0.7 mL) with stirring. After 2 hour at roomtemperature, the mixture was extracted with CH₂Cl₂ (10 mL) and theextract was washed with 0.5 N NaOH, and brine and dried over sodiumsulfate. The CH₂Cl₂ solution was filtered through silica gel and thefiltrate was evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.15 g of ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoateas a white solid;. mp 83-85° C.; HRMS: calcd for C₄₁H₃₆Cl₃FN₂O₅S,792.1395; found (ESI+), 793.14729.

Step 2: Ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate(0.11 g, 0.14 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL)were stirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland extracted with ethyl acetate. The extract was dried over sodiumsulfate, and evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.10 g of4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid as a white solid; mp 117-119° C.; HRMS: calcd for C₃₉H₃₂Cl₃FN₂O₅S,764.1082; found (ESI+), 787.09794

EXAMPLE 2974-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid

Step 1: [(2-chlorophenyl)methyl]sulfonyl chloride (0.14 g, 0.6 mmol) wasadded to a mixture of ethyl4-{2-[2-(2-Aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-fluoro-benzoate(Step 6, Example 190, 0.12 g, 0.2 mmol) and K₂CO₃ (0.11 g, 0.8 mmol) inCH₂Cl₂ (2 mL) and water (1 mL) with stirring. After 2 hour at roomtemperature, the mixture was extracted with CH₂Cl₂ (10 mL) and theextract was washed with 0.5 N NaOH, and brine and dried over sodiumsulfate. The CH₂Cl₂ solution was filtered through silica gel and thefiltrate was evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.07 g of ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoateas a white solid.

Step 2: Ethyl4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate(0.06 g, 0.1 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL)were stirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland extracted with ethyl acetate. The extract was dried over sodiumsulfate, and evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.06 g of4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid as an off-white solid; mp 132-135° C.; MS (ESI) m/z 729.74((M−H)−); HRMS: calcd for C₃₉H₃₃Cl₂FN₂O₅S, 730.1471; found (ESI+),731.15514.

EXAMPLE 2983-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoicacid

Step 1: [(3,4-chlorophenyl)methyl]sulfonyl chloride (0.06 g, 0.2 mmol)was added to a mixture of ethyl3-(4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethanesulfonyl}-phenyl)-2,2-dimethyl-propionate(0.09 g, 0.14 mmol) and K₂CO₃ (0.04 g, 0.28 mmol) in CH₂Cl₂ (2 mL) andwater (0.7 mL) with stirring. After 2 hour at room temperature, themixture was extracted with CH₂Cl₂ (10 mL) and the extract was washedwith 0.5 N NaOH, and brine and dried over sodium sulfate. The CH₂Cl₂solution was filtered through silica gel and the filtrate wasevaporated. The resulting residue was triturated with a mixture of etherand hexanes to give 0.04 g of ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoateas a white solid.

Step 2: Ethyl3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino)-ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoate(0.04 g, 0.05 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL)were stirred together overnight. Solvents were removed and the resultingresidue was taken up in water. The solution was acidified with 1N HCland extracted with ethyl acetate. The extract was dried over sodiumsulfate, and evaporated. The resulting residue was triturated with amixture of ether and hexanes to give 0.04 g of3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoicacid as a white solid; mp 207-208° C.; MS (ESI) m/z 849.1 (M−H); HRMS:calcd for C₄₃H₄₁Cl₃N₂O₆S₂, 850.1472; found (ESI+), 851.1545.

EXAMPLE 2994-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-methoxybenzoicacid

Step 1: 2,4-Dihydroxy-benzoic acid methyl ester (11.76 g, 70 mmol) wasdissolved in Et₂O (175 mL). Then Et₃N (10.78 mL, 77 mmol), Ac₂O (7.28mL, 77 mmol), and DMAP (catalytic amount) were added. The reactionsolution was then stirred for one hour at room temperature. Then thereaction solution was concentrated by rotary evaporation and theresulting residue was purified with a silica gel column anddichloromethane as eluent. Obtained 3.44 g 4-Acetoxy-2-hydroxy-benzoicacid methyl ester in 23% yield.

Step 2: MeOH (0.3 mL, 7.4 mmol) was added to the product from step 1(0.962 g, 4.6 mmol), Ph₃P (1.79 g, 6.8 mmol), and dichloromethane (10mL). Then DEAD (1.32 mL, 8.4 mmol) was added to the reaction. Reactionwas stirred at room temperature for 4 days. Reaction solution wasconcentrated by rotary evaporation and the resulting residue waspurified with silica gel prep plates and 1:3 EtOAc/Hexane as eluent.Obtained 1.10 g of 4-Acetoxy-2-methoxy-benzoic acid methyl ester inquantitative yield.

Step 3: 0.1N NaOH (10 mL, 1 mmol) was added to a solution of the productof step 2 (1.10 g, 4.9 mmol) in THF (1 mL) and MeOH (1 mL). Reaction wasstirred for three days at room temperature. Reaction solution wasconcentrated by rotary evaporation and resulting residue was dissolvedin water. The solution was neutralized with 1N HCl and a precipitateformed. Collected precipitate and washed with water and hexane. Obtained0.29 g of 4-Hydroxy-2-methoxy-benzoic acid methyl ester in 33% yield.

Step 4:2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142, 0.503 g, 0.78 mmol) was added to a mixture ofHydroxy-2-methoxy-benzoic acid methyl ester (0.29 g, 1.6 mmol), Ph₃P(0.312 g, 1.2 mmol), and dichloromethane (10 mL). Then DEAD (0.2 mL, 1.3mmol) was added to the reaction. Reaction was stirred at roomtemperature overnight. Reaction solution was concentrated by rotaryevaporation and the resulting residue was purified with silica gel prepplates and dichloromethane as eluent. Obtained 0.25 g of4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-methoxy-benzoicacid methyl ester in 40% yield.

Step 5: TBAF (1M in THF) (0.37 mL, 0.37 mmol) was added to a solution of4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-methoxy-benzoicacid methyl ester (0.25 g, 0.31 mmol) in THF (4 mL). Reaction wasstirred at room temperature for 30 minutes. Reaction solution wasconcentrated by rotary evaporation and the resulting residue waspurified with silica gel prep plates and 1:9 EtOAc/dichloromethane aseluent. Obtained 0.11 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester (white solid) in 62% yield.

Step 6: MeSO₂Cl (0.03 mL, 0.39 mmol) and Et₃N (0.07 mL, 0.48 mmol) wereadded to a solution of the alcohol from step 5 (0.11 g, 0.19 mmol) indichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for onehour and then warmed to room temperature and stirred an additional hour.Reaction solution was concentrated by rotary evaporation. Obtained 0.123g of4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester in quantitative yield.

Step 7: The mesylate from above (0.123 g, 0.19 mmol) was dissolved inDMF (5 mL). NaN₃ (0.065 g, 1.0 mmol) was added and the mixture washeated to 60° C. and stirred for three hours. Reaction was cooled toroom temperature and water was added. Extracted with EtOAc and washedorganic layer with brine. Dried organics over sodium sulfate andfiltered and concentrated by rotary evaporation. Dried further under astrong vacuum. Obtained 0.110 g of4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester in 97% yield.

Step 8: Ph₃P (polymer support: 3 mmol Ph₃P/gram) (0.110 g, 0.33 mmol)was added to a solution of the azide from step 7 (0.110 g, 0.18 mmol) inTHF (2 mL). Reaction was stirred at room temperature for 24 hours. Thenwater (0.5 mL) was added and reaction was stirred at room temperatureovernight. Reaction solution was filtered and the filtrate wasconcentrated by rotary evaporation. The resulting residue was purifiedwith silica gel prep plates and 2% MeOH in dichloromethane as eluent.Obtained 0.012 g of4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoicacid methyl ester in 12% yield.

Step 9: An aqueous, saturated solution of Na₂CO₃ (2 mL) was added to asolution of the amine from step 8 (0.012 g, 0.021 mmol) and[(3,4-dichlorophenyl)methyl]sulfonyl chloride (0.010 g, 0.039 mmol) indichloromethane (2 mL). Reaction was stirred at room temperature for twohours. The reaction solution was then separated and the organic phasewas collected and washed with brine and dried over sodium sulfate.Filtered and concentrated the organic solution by rotary evaporation.The resulting residue was purified with silica gel prep plates and 2%MeOH in dichloromethane as eluent. Obtained 0.016 g of the desiredsulfonamide (white solid) in 96% yield. m/z (M+1) 793

Step 10: 1N NaOH (1 mL) was added to a solution of the ester from step 9(0.016 g, 0.020 mmol) in THF (1 mL) and MeOH (1 mL). Reaction wasstirred at room temperature for five days. The THF and MeOH were removedby rotary evaporation. Extracted with dichloromethane and separated andcollected the aqueous layer. Neutralized the aqueous layer with 1N HCland collected the resulting precipitate. Obtained 0.013 g of the titleacid (yellow solid) in 84% yield. m/z (M−1) 777

EXAMPLE 3004-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoicacid

Step 1: Isopropanol (0.63 mL, 8.2 mmol) was added to a mixture of4-Acetoxy-2-methoxy-benzoic acid methyl ester (Step 1, Example 299, 1.18g, 5.6 mmol), Ph₃P (1.84 g, 7.0 mmol), and dichloromethane (15 mL). ThenDEAD (1.12 mL, 7.1 mmol) was added to the reaction. Reaction was stirredat room temperature for two days. Reaction solution was concentrated byrotary evaporation and the resulting residue was purified with silicagel prep plates and 1:5 EtOAc/Hexane as eluent. Obtained 1.11 g of4-Acetoxy-2-isopropoxy-benzoic acid methyl ester in 79% yield.

Step 2: 0.1N NaOH (10 mL, 1 mmol) was added to a solution of4-Acetoxy-2-isopropoxy-benzoic acid methyl ester (0.910 g, 3.6 mmol) inTHF (1 mL) and MeOH (1 mL). Reaction was stirred for three days at roomtemperature. Reaction solution was concentrated by rotary evaporationand resulting residue was dissolved in water. The solution wasneutralized with 1N HCl and a precipitate formed. Collected precipitateand washed with water and hexane. Obtained 0.870 g of4-Hydroxy-2-isopropoxy-benzoic acid methyl ester in quantitative yield.

Step 3:2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethanol(Step 6, Example 142, 0.500 g, 0.78 mmol) was added to a mixture of4-Hydroxy-2-isopropoxy-benzoic acid methyl ester (0.328 g, 1.6 mmol),Ph₃P (0.312 g, 1.2 mmol), and dichloromethane (10 mL). Then DEAD (0.2mL, 1.3 mmol) was added to the reaction. Reaction was stirred at roomtemperature overnight. Reaction solution was concentrated by rotaryevaporation and the resulting residue was purified with silica gel prepplates and dichloromethane as eluent. Obtained 0.20 g of4-(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)-2-isopropoxy-benzoicacid methyl ester in 31% yield.

Step 4: TBAF (1M in THF) (0.29 mL, 0.29 mmol) was added to a solution ofthe silyl ether from step 3 (0.20 g, 0.24 mmol) in THF (4 mL). Reactionwas stirred at room temperature for 30 minutes. Reaction solution wasconcentrated by rotary evaporation and the resulting residue waspurified with silica gel prep plates and 1:9 EtOAc/dichloromethane aseluent. Obtained 0.10 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-hydroxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester (brown solid) in 70% yield.

Step 5: Methane sulfonyl chloride (0.03 mL, 0.39 mmol) and Et₃N (0.06mL, 0.43 mmol) were added to a solution of the alcohol from Step 4 (0.10g, 0.17 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at0° C. for one hour and then warmed to room temperature and stirred anadditional hour. Reaction solution was concentrated by rotaryevaporation. Obtained 0.115 g of4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester in quantitative yield.

Step 6: The mesylate from Step 5 (0.115 g, 0.17 mmol) was dissolved inDMF (5 mL). NaN₃ (0.065 g, 1.0 mmol) was added and the mixture washeated to 60° C. and stirred for three hours. Reaction was cooled toroom temperature and water was added. Extracted with EtOAc and washedorganic layer with brine. Dried organics over sodium sulfate andfiltered and concentrated by rotary evaporation. Dried further under astrong vacuum. Obtained 0.100 g of4-{2-[2-(2-Azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester in 94% yield.

Step 7: Ph₃P (polymer support: 3 mmol Ph₃P/gram) (0.100 g, 0.30 mmol)was added to a solution of the azide from Step 6 (0.100 g, 0.16 mmol) inTHF (2 mL). Reaction was stirred at room temperature for 24 hours. Thenwater (0.5 mL) was added and reaction was stirred at room temperatureovernight. Reaction solution was filtered and the filtrate wasconcentrated by rotary evaporation. The resulting residue was purifiedwith silica gel prep plates and 2% MeOH in dichloromethane as eluent.Obtained 0.020 g of4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoicacid methyl ester in 21% yield.

Step 8: An aqueous, saturated solution of Na₂CO₃ (2 mL) was added to asolution of the amine from Step 7 (0.020 g, 0.034 mmol) and[(3,4-dichlorophenyl)methyl]sulfonyl chloride (0.015 g, 0.058 mmol) indichloromethane (2 mL). Reaction was stirred at room temperature for twohours. The reaction solution was then separated and the organic phasewas collected and washed with brine and dried over sodium sulfate.Filtered and concentrated the organic solution by rotary evaporation.The resulting residue was purified with silica gel prep plates and 2%MeOH in dichloromethane as eluent. Obtained 0.022 g of the desiredsulfonamide (white solid) in 79% yield. m/z (M+1) 821

Step 9: 1N NaOH (1 mL) was added to a solution of the ester from Step 8(0.022 g, 0.027 mmol) in THF (1 mL) and MeOH (1 mL). Reaction wasstirred at room temperature for five days. The THF and MeOH were removedby rotary evaporation. Extracted with dichloromethane and separated andcollected the aqueous layer. Neutralized the aqueous layer with 1N HCland collected the resulting precipitate. Obtained 0.021 g of the titleacid (yellow solid) in 96% yield. m/z (M−1) 805

Activity Assay

Coumarine Assay

7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate forcPLA2 as reported previously (Huang, Z. et al., 1994, NalyticalBiochemistry 222, 110-115). Inhibitors were mixed with 200 μL assaybuffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing 60 μM7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by adding 4μg cPLA2 in 50 μL assay buffer. Hydrolysis of the 7-hydroxycounarimyl6-heptenoate ester was monitored in a fluorometer by exciting at 360 nmand monitoring emission at 460 nm. Enzyme activity is proportional tothe increase in emission at 460 nm per minute. In the presence of acPLA2 inhibitor, the rate of increase is less.

Coumarin Example # IC₅₀ (uM) Example 1 0.42 Example 2 2 Example 3 2.5Example 4 56 Example 5 3 Example 6 2.0 Example 7 0.55 Example 8 2Example 9 0.7 Example 10 0.57 Example 11 0.45 Example 12 150 Example 130.64 Example 14 0.8 Example 15 0.63 Example 16 0.98 Example 17 0.2Example 18 0.4 Example 19 0.31 Example 20 1.1 Example 21 1.1 Example 221.8 Example 23 1.5 Example 24 0.34 Example 25 3.4 Example 26 1.1 Example27 0.8 Example 28 0.95 Example 29 0.19 Example 30 0.15 Example 31 0.15Example 32 0.085 Example 33 2.9 Example 35 0.33 Example 36 0.5 Example37 0.37 Example 38 0.5 Example 39 0.32 Example 40 0.73 Example 41 0.2Example 42 0.18 Example 43 0.2 Example 44 0.25 Example 45 4.7 Example 464.8 Example 47 0.58 Example 48 2.35 Example 49 1.1 Example 50 0.69Example 51 2.2 Example 52 0.13 Example 53 0.37 Example 54 0.31 Example55 0.26 Example 56 0.13 Example 57 0.28 Example 58 0.36 Example 59 0.29Example 60 0.15 Example 61 0.34 Example 62 0.38 Example 63 0.30 Example64 0.12 Example 65 0.13 Example 66 0.15 Example 67 0.14 Example 68 0.16Example 69 0.15 Example 70 0.18 Example 71 0.45 Example 72 0.28 Example73 0.30 Example 74 0.28 Example 75 0.4 Example 76 0.4 Example 77 0.48Example 78 0.34 Example 79 0.15 Example 80 3.7 Example 81 0.47 Example82 0.5 Example 83 0.45 Example 84 0.5 Example 85 0.4 Example 86 0.6Example 87 1.2 Example 88 <7.4 Example 89 0.38 Example 90 0.65 Example91 0.5 Example 92 1.0 Example 93 0.56 Example 94 0.8 Example 95 0.85Example 96 0.95 Example 97 0.95 Example 98 1.1 Example 99 1.0 Example100 0.12 Example 101 0.1 Example 102 0.19 Example 103 1.1 Example 1041.1 Example 105 0.65 Example 106 0.22 Example 107 0.33 Example 108 0.15Example 109 0.4 Example 110 0.5 Example 111 1.0 Example 112 1.2 Example113 1.3 Example 114 1.1 Example 115 0.9 Example 116 1.2 Example 117 1.6Example 118 0.4 Example 119 0.4 Example 120 0.4 Example 121 0.46 Example122 2.5 Example 123 1.5 Example 124 0.8 Example 125 1.4 Example 126 0.2Example 127 0.2 Example 128 0.32 Example 129 0.13 Example 130 0.17Example 131 0.2 Example 132 0.2 Example 133 0.09 Example 134 >1 Example135 0.2 Example 136 0.18 Example 137 NT Example 138 0.2 Example 139 1.7Example 140 0.2 Example 141 0.17 Example 142 NT Example 143 NT Example144 NT Example 145 NT Example 146 NT Example 147 NT Example 148 NTExample 149 NT Example 150 NT Example 151 NT Example 152 0.32 Example153 0.16 Example 154 0.35 Example 155 0.45 Example 156 0.16 Example 1570.2 Example 158 0.2 Example 159 0.65 Example 160 0.19 Example 161 0.32Example 162 1.0 Example 163 0.3 Example 164 0.2 Example 165 0.53 Example166 0.4 Example 167 0.19 Example 168 0.27 Example 169 0.46 Example 1700.95 Example 171 0.36 Example 172 0.35 Example 173 0.4 Example 174 1.1Example 175 0.37 Example 176 0.4 Example 177 0.9 Example 178 0.65Example 179 0.9 Example 180 0.23 Example 181 0.32 Example 182 0.6Example 183 0.17 Example 184 0.35 Example 185 0.17 Example 186 0.1Example 187 0.2 Example 188 NT Example 189 NT Example 190 0.53 Example191 0.2 Example 192 <3.7 Example 193 1.8 Example 194 1 Example 195 1Example 196 0.56 Example 197 0.4 Example 198 0.7 Example 199 0.45Example 200 0.35 Example 201 0.35 Example 202 0.3 Example 203 0.69Example 204 0.2 Example 205 0.37 Example 206 0.5 Example 207 1.4 Example208 0.24 Example 209 0.35 Example 210 0.15 Example 211 0.4 Example 2120.18 Example 213 0.45 Example 214 NT Example 215 NT Example 216 NTExample 217 2.6 Example 218 0.14 Example 219 0.4 Example 220 0.4 Example221 0.5 Example 222 0.19 Example 223 0.6 Example 224 0.25 Example 2250.4 Example 226 0.14 Example 227 0.16 Example 228 0.4 Example 229 0.5Example 230 0.15 Example 231 0.25 Example 232 0.13 Example 233 0.34Example 234 0.23 Example 235 0.18 Example 236 0.085 Example 237 0.2Example 238 0.25 Example 239 0.48 Example 240 0.32 Example 241 0.54Example 242 1.3 Example 243 0.75 Example 244 1.3 Example 245 0.9 Example246 1.2 Example 247 1.2 Example 248 1.2 Example 249 0.67 Example 250 2.1Example 251 1.5 Example 252 0.73 Example 253 0.75 Example 254 0.26Example 255 0.5 Example 256 0.6 Example 257 0.5 Example 258 0.8 Example259 0.2 Example 260 0.37 Example 261 0.25 Example 262 0.53 Example 2630.32 Example 264 0.4 Example 265 0.37 Example 266 0.16 Example 267 0.074Example 268 0.09 Example 269 0.15 Example 270 0.14 Example 271 0.15Example 272 0.1 Example 273 0.11 Example 274 NT Example 275 0.24 Example276 0.32 Example 277 0.6 Example 278 1.9 Example 279 0.16 Example 2800.35 Example 281 NT Example 282 NT Example 283 0.5 Example 284 0.4Example 285 NT Example 286 NT Example 287 0.42 Example 288 0.4 Example289 0.9 Example 290 NT Example 291 NT Example 292 NT Example 293 NTExample 294 NT Example 295 0.55 Example 296 0.32 Example 297 0.3 Example298 0.19 Example 299 1.0 Example 300 >2

The compounds of the invention inhibit cPLA2 activity that is requiredfor supplying arachidonic acid substrate to cyclooxygenase-1or 2 and5-lipoxygenase, which in turn initiate the production of prostaglandinsand leukotrienes respectively. In addition, cPLA2 activity is essentialfor producing the lyso-phospholipid that is the precursor to PAF. Thusthese compounds are useful in the treatment and prevention of diseasestates in which leukotrienes, prostaglandins or PAF are involved.Moreover, in diseases where more than one of these agents plays a role,a cPLA2 inhibitor would be expected to be more efficacious thanleukotriene, prostaglandin or PAF receptor antagonists and also moreeffective than cyclooxygenase or 5-lipoxygenase inhibitors.

Therefore, the compounds, pharmaceutical compositions and regimens ofthe present invention are useful in treating and preventing thedisorders treated by cyclooxygenase-2, cycloxygenase-1, and5-lipoxygenase inhibitors and also antagonists of the receptors for PAF,leukotrienes or prostaglandins. Diseases treatable by compounds of thisinvention include but are not limited to: pulmonary disorders includingdiseases such as asthma, chronic bronchitis, and related obstructiveairway diseases; allergies and allergic reactions such as allergicrhinitis, contact dermatitis, allergic conjunctivitis, and the like;inflammation such as arthritis or inflammatory bowel diseases, skindisorders such as psoriasis, atopic eczema, acne, UV damage, burns anddermatittis; cardiovascular disorders such as atherosclerosis, angina,myocardial ischaemia, hypertension, platelet aggregation, and the like;and renal insufficiency induced by immunological or chemical. The drugsmay also be cytoprotective, preventing damage to the gastrointestinalmucosa by noxious agents. The compounds will also be useful in thetreatment of adult respiratory distress syndrome, endotoxin shock andischeamia induced injury including myocardial or brain injury.

The methods of treatment, inhibition, alleviation or relief of asthma ofthis invention include those for Extrinsic Asthma (also known asAllergic Asthma or Atopic Asthma), Intrinsic Asthma (also known asNonallergic Asthma or Nonatopic Asthma) or combinations of both, whichhas been referred to as Mixed Asthma. The methods for those experiencingor subject to Extrinsic or Allergic Asthma include incidents caused byor associated with many allergens, such as pollens, spores, grasses orweeds, pet danders, dust, mites, etc. As allergens and other irritantspresent themselves at varying points over the year, these types ofincidents are also referred to as Seasonal Asthma. Also included in thegroup of Extrinsic Asthmas is bronchial asthmas and allergicbronchopulminary aspergillosis.

Intrinsic Asthmas that may be treated or alleviated by the presentmethods include those caused by infectious agents, such as cold and fluviruses in adults and respiratory syncytial virus (RSV), rhinovirus andinfluenza viruses common in children. Also included are the asthmaconditions which may be brought about in some asthmatics by exerciseand/or cold air. The methods are useful for Intrinsic Asthmas associatedwith industrial and occupational exposures, such as smoke, ozone,noxious gases, sulfur dioxide, nitrous oxide, fumes, includingisocyanates, from paint, plastics, polyurethanes, varnishes, etc., wood,plant or other organic dusts, etc. The methods are also useful forasthmatic incidents associated with food additives, preservatives orpharmacological agents. Common materials of these types are foodcoloring such as Tartrazine, preservatives like bisulfites andmetabisulfites, and pharmacological agents such as aspirin andnon-steroidal anti-inflammatory agents (NSAIDs). Also included aremethods for treating, inhibiting or alleviating the types of asthmareferred to as Silent Asthma or Cough Variant Asthma.

The methods herein are also useful for treatment and alleviation ofIntrinsic Asthma associated with gastroesophageal reflux (GERD), whichcan stimulate bronchoconstriction. GERD, along with retained bodilysecretions, suppressed cough, and exposure to allergens and irritants inthe bedroom can contribute to asthmatic conditions and have beencollectively referred to as Nighttime Asthma or Nocturnal Asthma. Inmethods of treatment, inhibition or alleviation of asthma associatedwith GERD, a pharmaceutically effective amount of the compounds of thisinvention may be used as described herein in combination with apharmaceutically effective amount of an agent for treating GERD. Theseagents include, but are not limited to, proton pump inhibiting agentslike PROTONIX® brand of delayed-release pantoprazole sodium tablets,PRILOSEC® brand omeprazole delayed release capsules, ACIPHEX® brandrebeprazole sodium delayed release tablets or PREVACID® brand delayedrelease lansoprazole capsules.

The compounds of this invention may also be administered in the methodsof this invention with analgesic and anti-inflammatory agents such asNSAIDs and aspirin and other salicylates. Examples of useful agentsinclude ibuprofen (MOTRIN®, ADVIL®), naproxen (NAPROSYN®), sulindac(CLINORIL®), diclofenac (VOLTAREN®), piroxicam (FELDENE®) ketoprofen(ORUDIS®), diflunisal (DOLOBID®), nabumetone (RELAFEN®), etodolac(LODINE®), oxaprozin (DAYPRO®), indomethacin (INDOCIN®), melicoxam(MOBICOX®), valdecoxib and eterocoxib. Aspirin is anti-inflammatory whengiven in high doses, otherwise it is just a pain killer likeacetaminophen (TYLENOL®).

Suitable cyclooxygenase 2 (COX-2) inhibitors for use with the methods ofthis invention include, but are not limited to,2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,CDC-501, celecoxib, COX-189,4-(2-oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, CS-179,CS-502, D-1367, darbufelone, DFP, DRF-4367, flosulide, JTE-522(4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide),L-745337, L-768277, L-776967, L-783003, L-791456, L-804600, meloxicam,MK663 (etoricoxib), nimesulide, NS-398, parecoxib,1-Methylsulfonyl-4-(1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl)benzene,4-(1,5-Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-c)pyrazol-1-yl)benzenesulfonamide,4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl) cyclobutenone,4-Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzenesulfonamide,1-(7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropylbutan-1-one, Pharmaprojects No. 6089 (Kotobuki Pharmaceutical),RS-113472, RWJ-63556, S-2474, S-33516, SC-299, SC-5755, valdecoxib,UR-8877, UR-8813, UR-8880. Further suitable COX-2 inhibitors for useaccording to the invention include parecoxib, MK663,4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide(JTE-522), nimesulide, flosulide, DFP and2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine,and their physiologically acceptable salts, esters or solvates.

Each of the methods of this invention comprises administering to amammal in need of such treatment a pharmaceutically or therapeuticallyeffective amount of a compound of this invention. In the instances ofcombination therapies described herein, it will be understood theadministration further includes a pharmaceutically or therapeuticallyeffective amount of the second pharmaceutical agent in question. Thesecond or additional pharmacological agents described herein may beadministered in the doses and regimens known in the art.

The compounds of this invention may also be used in comparableveterinary methods of treatment, particularly for the veterinarytreatment, inhibition or alleviation of inflammation and pain associatedwith asthmatic conditions. These methods will be understood to be ofparticular interest for companion mammals, such as dogs and cats,particularly with feline asthma. These compounds may also be used in thetreatment of inflammation of the air passages, such as in conditions ofasthma, laryngitis, tracheitis, bronchitis, rhinitis and pharyngitis

The compounds of this invention may be used in the veterinary treatmentof asthma and asthmatic conditions in combination with other treatmentsfor asthma, such as feline asthma, including oral or injectablesteroids, Cyproheptadine, Cyclosporin A, or Anti-Interleukin-5 Antibody.

Each of these veterinary methods comprises administering to the mammalin need thereof a pharmaceutically effective amount of a compound ofthis invention, or a pharmaceutically acceptable salt form thereof. Thecompounds of this invention may be used for human or veterinary methodsin conjunction with other medicaments or dietary supplements known inthe art for the treatment, inhibition or alleviation of inflammation orpain. These may include aspirin (including buffered aspirin, aspirinwith Maalox and enteric coated aspirin), COX-2 inhibitors, such ascelecoxib, non-acetylated carboxylic acids, such as magnesiumsalicylate, salicylamide or sodium salicylate, acetic acids, such asdoclofenac or etodolac, propionic acids, such as ibuprofen, naproxen(available in NAPROSYN® and EQUIPROXEN® brands), ketoprofen, RIMADYL®(carprofen), flunixin meglumine, fenamic acids, such as tolfenamic acid,mefanamic acid, meclofenamic acid (ARQUEL®) or niflumic acid, enolicacids, such as oxyphenbutazone, phenylbutazone, piroxicam or dipyrone,or non-acidic compounds like nabumetone. Also used in veterinaryapplications are dimethylsulfoxide (DMSO), orgotein (such as PALOSEIN®brand of orgotein), polysulfated glycosaminoglycans or PS-GAGs (such asADEQUAN® brand polysulfated glycosaminoglycan), hyaluronic acid and itsnatural and synthetic analogues, Ketorolac trimethamine (such as theTORADOL® brand), FELDENE® (piroxicam), or METACAM® (meloxicam).

Dietary supplements used in human or veterinary applications includeglucosamines, chondroitin sulfate, methylsulfonylmethane (MSM), andomega 3 fatty acids and other cold water fish oils. The compounds andmethods of this invention may also be used in conjunction with human orveterinary physical therapy, massage, chiropractic and accupuncturetreatments and regimens. Each of these medicaments and dietarysupplements may be administered to the mammal in question using regimensand effective dosages known in the art.

1. A method of treatment of asthma in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of the formula:

wherein: R is —(CH₂)_(n)-A, wherein A is:

wherein B and C are each phenyl, each independently optionallysubstituted by from 1 to 3 substituents selected independently fromhalogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂,—N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and —NO₂; nis an integer from 0 to 3; n₁ is an integer from 1 to 3; n₂ is aninteger from 0 to 4; n₃ is an integer from 0 to 3; n₄ is an integer from0 to 2; X₁ is selected from a chemical bond, —S—, —O—, —S(O)—, —S(O)₂—,—NH—, —NHC(O)—, —C═C—,

R₁ is selected from C₁-C₆ alkyl, C₁-C₆ fluorinated alkyl, C₃-C₆cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, CN, —N(C₁-C₆alkyl)₂, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, napthyl,morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl,imidazolyl, piperazinyl, thiazolidinyl, thiomorpholinyl, tetrazolyl,indolyl, benzoxazolyl, benzofuranyl, imidazolidine-2-thionyl,7,7-dimethyl-bicyclo[2.2.1]heptan-2-onyl, benzo[1,2,5]oxadiazolyl,2-oxa-5-aza-bicyclo[2.2.1]heptanyl, piperazin-2-onyl, and pyrrolylgroups, each optionally substituted by from 1 to 3 substituentsindependently selected from halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, C₁-C₆alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), —NO₂, —SO₂(C₁-C₃ alkyl, —SO₂NH₂, —SO₂NH(C₁-C₃alkyl), —SO₂N(C₁-C₃ alkyl)₂, —COOH, —CH₂—COOH, —CH₂—NH(C₁-C₆ alkyl),—CH₂—N(C₁-C₆ alkyl)₂, —CH₂—NH₂, pyridinyl, 2-methyl-thiazolyl,morpholino, 1-chloro-2-methyl-propyl, C₁-C₆thioalkyl, phenyl (furtheroptionally substituted with one or more halogens), benzyloxy, —(C₁-C₃alkyl)C(O)CH₃, —(C₁-C₃ alkyl)OCH₃, —C(O)NH₂,

X₂ is selected from —O—, —CH₂—, —S—, —SO—, —SO₂—, —NH—, —C(O)—,

R₂ is phenyl substituted by a group of the formula —(CH₂)_(n4)—CO₂H or apharmaceutically acceptable acid mimic or mimetic; and also optionallysubstituted by 1 or 2 additional substituents independently selectedfrom halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), and —NO₂; R₃ is H, halogen, —CN, —CHO, —CF₃,—OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), or —NO₂; and R₄ is H,halogen, —CN, —CHO, —CF₃, —OCF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆alkyl), —NO₂, morpholino, pyrrolidino, piperidinyl, or piperizinyl; or apharmaceutically acceptable salt thereof.
 2. A method of claim 1 whereinR₂ is selected from the group consisting of:

wherein R_(a) is selected from —CF₃, —CH₃, phenyl, or benzyl, with thephenyl or benzyl groups being optionally substituted by from 1 to 3groups selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —CF₃,halogen, —OH, or —COOH; R_(b) is selected from —CF₃, —CH₃, —NH₂, phenyl,and benzyl, with the phenyl or benzyl groups being optionallysubstituted by from 1 to 3 groups selected from C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ thioalkyl, —CF₃, halogen, —OH, or —COOH; and R_(c) isselected from —CF₃ and C₁-C₆ alkyl.
 3. The method of claim 1 wherein Ais the moiety:


4. The method of claim 1, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof formulae (II):

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 4wherein n3=1.
 6. The method of claim 4 wherein R₂ is phenyl substitutedby a group of the formula —(CH₂)_(n4)—CO₂H; and optionally substitutedby 1 or 2 additional substituents independently selected from halogen,—CN, —CHO, —CF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂,—N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and NO₂. 7.A method of treatment of asthma in a mammal, the method comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of formulae (IV):

wherein: n₁ is an integer from 1 to 3; n₂ is an integer from 1 to 3; R₅,R₆ and R₇ are independently selected from H, halogen, —CN, —CHO, —CF₃,—OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), and —NO₂; X₁ is selected from a chemical bond,—S—, —O—, —NH—, and —N(C₁-C₃ alkyl)—; X₂ is selected from —O—, SO₂—, and—CH₂—; R₂ is a moiety selected from the group of:

R₈ and R₉ are independently selected from H, halogen, —CN, —CHO, —CF₃,—OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆alkyl), —NH—C(O)—(C₁-C₆ alkyl), and —NO₂; n₄ is an integer from 0 to 2;R₃ is H, halogen, —CN, —CHO, —CF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆alkyl), or —NO₂; and R₄ is H, halogen, —CN, —CHO, —CF₃, —OH, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆alkyl), —NH—C(O)—(C₁-C₆ alkyl), —NO₂, morpholino, pyrrolidino,piperidinyl, or piperizinyl; or a pharmaceutically acceptable saltthereof.
 8. A method of treatment of asthma in a mammal, the methodcomprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of the formulae (VI):

wherein: X₁ is selected from a chemical bond, —S—, —O—, —NH—, and—N(C₁-C₃ alkyl)—; X₂ is selected from —O—, —SO₂—, and —CH₂—; R₃ is H,halogen, —CN, —CHO, —CF₃, —OH, —C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆alkyl), or —NO₂; R₄ is H, halogen, —CN, —CHO, —CF₃, —OH, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ thioalkyl, —NH₂, —N(C₁-C₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), —NO₂, morpholino, pyrrolidino, piperidinyl, orpiperizinyl; n₁ is an integer from 1 to 2; n₂ is an integer from 1 to 2;R₅, R₆ and R₇ are independently selected from H, halogen, —CN, —CHO,—CF₃, OCF₃, —OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NH₂, —N(C₁-C₆ alkyl)₂,—NH(C₁-C₆ alkyl), —NH—C(O)—(C₁-C₆ alkyl), and —NO₂; R₈ and R₉ areindependently selected from H, halogen, —CN, —CHO, —CF₃, —OH, C₁-C₆alkyl, C₁-C₆ alkoxy, —NH₂, —N(C_(1-C) ₆ alkyl)₂, —NH(C₁-C₆ alkyl),—NH—C(O)—(C₁-C₆ alkyl), and —NO₂; or a pharmaceutically acceptable saltthereof.
 9. The method of claim 8 wherein: n₁ is 1; and n₂ is
 1. 10. Themethod of claim 1, wherein X₁ is a chemical bond.
 11. The method ofclaim 3, wherein X₁ is a chemical bond.
 12. The method of claim 4,wherein X₁ is a chemical bond.
 13. The method of claim 7, wherein X₁ isa chemical bond.
 14. The method of claim 8, wherein X₁ is a chemicalbond.
 15. The method of claim 1 wherein the compound is selected from:4-[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[(isopropylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;4-[2-(1-Benzhydryl-2-{2-[(butylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid; and4-{2-[1-Benzhydryl-2-(2-{[(5-bromo-6-chloro-3-pyridinyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid; or a pharmaceuticallyacceptable salt thereof.
 16. The method of claim 1 wherein the compoundis selected from:4-[2-(1-Benzhydryl-5-chloro-2-{2-[({[(1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(methylsulfonyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(2-(1-naphthyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-{2-[({2-nitrobenzyl}-sulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 17. The method ofclaim 1 wherein the compound is selected from:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)-benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[(4-trifluoromethyl)-benzyl]sulfonyl}-amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 18. The method ofclaim 1 wherein the compound is selected from:4-{2-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-5-chloro-1-(diphenylmethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(dimethylamino)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,4-difluorobenzyl)sulfonyl]amino}-ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-naphthylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and3-({[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}methyl)benzoicacid; or a pharmaceutically acceptable salt thereof.
 19. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-benzhydryl-5-chloro-2-[2-({[(E)-2-phenylethenyl]sulfonyl}amino)ethyl]1H-indol-3-yl}ethoxy)benzoicacid;4-(2-[1-benzhydryl-5-chloro-2-(2-{[(trifluoromethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-2-[2-({[3,5-bis(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid; and2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}benzoicacid; or a pharmaceutically acceptable salt thereof.
 20. The method ofclaim 1 wherein the compound is selected from:4-[2-(1-benzhydryl-5-chloro-2-{2-[(2-naphthylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 21. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-morpholin-4-yl-1H-indol-′3-yl)ethoxy]benzoicacid4-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-morpholin-4-yl-1H-indol-3-yl)ethoxy]benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 22. The method ofclaim 1 wherein the compound is selected from:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-({[4-(1piperidinylsulfonyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{2-[2-({[4-(Aminosulfonyl)benzyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoicacid; and4-(2-{1-Benzhydryl-5-chloro-2-[2-(4-methanesulfonyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid; or apharmaceutically acceptable salt thereof.
 23. The method of claim 1wherein the compound is selected from:4-(2-{1-Benzhydryl-5-chloro-2-[2-(4-diethylsulfamoyl-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-{3-[1-Benzhydryl-5-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-propyl}-benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-[(methylsulfonyl)amino]ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 24. The method ofclaim 1 wherein the compound is selected from the group consisting of:4-{2-[1-benzhydryl-5-chloro-2-{2-[(phenylsulfonyl)amino]ethyl}-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;2-{[(2-{[(2-{1-benzhydryl-3-[2-(4-carboxyphenoxy)ethyl]-5-chloro-1H-indol-2-yl}ethyl)amino]sulfonyl}ethyl)amino]carbonyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-3-ylmethylsulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-4-ylmethylsulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 25. The method ofclaim 1 wherein the compound is selected from the group consisting of:4-{2-[1-benzhydryl-5-chloro-2-(2-{[pyridin-2-ylmethylsulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(cyclohexylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 26. The method ofclaim 1 wherein the compound is selected from:4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)benzyl]sulfonylamino)ethyl]-1H-indol-3-yl}propyl)benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)benzyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoicacid; and4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; or a pharmaceutically acceptable salt thereof.
 27. The method ofclaim 1 wherein the compound is selected from:4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-pyridinylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; and4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; or a pharmaceutically acceptable salt thereof.
 28. The method ofclaim 1 wherein the compound is selected from:4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[2-(2-{[(2-aminobenzyl)sulfonyl]amino}ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]propyl}benzoicacid; and4-{3-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; or a pharmaceutically acceptable salt thereof.
 29. The method ofclaim 1 wherein the compound is selected from:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(4-trifluoromethoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-fluoro-6-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2,5-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-2-{1-benzhydryl-5-chloro-2-[2-({[(6-chloro-3-pyridinyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; or a pharmaceutically acceptable salt thereof.
 30. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-benzhydryl-5-chloro-2-[2-({[(5,6-dichloropyridin-2-yl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-methoxybenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3,5-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-methylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2,6-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 31. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-benzhydryl-5-chloro-2[2({[(phenylsulfanyl)methyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dimethyl-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-methoxy-phenyl-sulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2-chloro-6-methylphenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid; and 4-(2-{1-benzhydryl-5-chloro-2-[2-(3,5-dichloro-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid; or apharmaceutically acceptable salt thereof.
 32. The method of claim 1wherein the compound is selected from:4-(2-{1-benzhydryl-5-chloro-2-[2-(3,4-dimethoxy-phenylsulfanylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin-4-ylethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-phenylamino-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; and4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; or a pharmaceutically acceptable salt thereof.
 33. The method ofclaim 1 wherein the compound is selected from:4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[4-(2-pyridinyl)-1-piperazinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1H-1,2,4-triazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methyl-1H-pyrazol-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; or a pharmaceutically acceptable salt thereof.
 34. The method ofclaim 1 wherein the compound is selected from:4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2R,6S)-2,6-dimethyl-1-piperidinyl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-thioxo-1-imidazolidinyl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(1,3-thiazolidin-3-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-[1,2,3]triazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and4-(3-{1-Benzhydryl-5-chloro-2-[2-(2-morpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid; or a pharmaceutically acceptable salt thereof.
 35. The method ofclaim 1 wherein the compound is selected from:4-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(2,6-dimethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl)-1H-indol-3-yl)-propyl]-benzoicacid;4-[3-(1-Benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-pyrazol-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-propyl]-benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-2-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-tetrazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}ethoxy)benzoicacid; and4-{2-[1-Benzhydryl-6-chloro-2-(2-phenylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid; or a pharmaceutically acceptable salt thereof.
 36. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,4-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-6-chloro-2-[2-(3,5-dichloro-phenylmethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(2-cyanobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(tetrahydro-2H-pyran-2-ylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid; and4-{2-[1-Benzhydryl-2-(2-{[(1,3-benzoxazol-2-ylmethyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid; or a pharmaceutically acceptable salt thereof.
 37. The method ofclaim 1 wherein the compound is selected from:4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(cyanomethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-Benzhydryl-5-chloro-2-(2-{[(3-thienylmethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid; and4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2,5-dimethyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid; or a pharmaceutically acceptable salt thereof.
 38. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-thiomorpholin-4-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-piperidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-o-tolylsulfanylmethanesulfonylamino-ethyl)-1H-indol-3-yl]-ethoxy}-benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-phenylsulfanylmethane-sulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; or4-(2-{1-benzhydryl-5-chloro-2-[2-(2,6-dichloro-phenylsulfanylmethane-sulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid; or a pharmaceuticallyacceptable salt thereof.
 39. The method of claim 1 wherein the compoundis selected from: 4-(2-{1-benzhydryl-5-chloro-2-[2-(2,5-dimethoxy-phenylsulfanyl-methanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3-hydroxy-pyrrolidine-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid;4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(4-hydroxy-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid;4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; and4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-dimethylaminomethyl-piperidin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoicacid; or a pharmaceutically acceptable salt thereof.
 40. The method ofclaim 1 wherein the compound is selected from:4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-imidazol-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid; and3-(4-{[2-(1-Benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]sulfonyl}phenyl)propanoicacid; or a pharmaceutically acceptable salt thereof.
 41. The method ofclaim 1 wherein the compound is selected from:3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoicacid;4-({[(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl)-5-chloro-1H-indol-3-yl)methyl]amino}methyl)benzoicacid; and4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3yl)ethyl]sulfonyl}benzoicacid; or a pharmaceutically acceptable salt thereof.
 42. The method ofclaim 1 wherein the compound is selected from:4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoicacid; and4-(2-{1-Benzhydryl-5-chloro-2-[2-(2-pyrrolidin-1-yl-ethanesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoicacid; or a pharmaceutically acceptable salt thereof.
 43. The method ofclaim 1 wherein the compound is selected from:4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)1H-indol-3-yl]ethyl}sulfonyl)benzoicacid; and4-[2-(1-benzhydryl-2-{3-[(benzylsulfonyl)amino]propyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoicacid; or a pharmaceutically acceptable salt thereof.
 44. The method ofclaim 1, wherein the compound is selected from:4-{[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl]amino}benzoic acid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoic acid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}amino)benzoicacid;4-[[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethyl](methyl)amino]benzoic acid;4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoicacid;4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;4-[{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)-sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}(methyl)amino]benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]-amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-(3-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}propyl)benzoic acid;4-[3-(1-benzhydryl-2-{2-[(1,1′-biphenyl-2-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoic acid;4-{3-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-cyanophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-(2-{2-[2-({[2-(aminomethyl)phenyl]sulfonyl}amino)ethyl]-1-benzhydryl-5-chloro-1H-indol-3-yl}ethoxy)benzoic acid;4-[2-(1-benzhydryl-2-{2-[(1,1′-biphenyl-2-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)ethoxy]benzoic acid;4-{2-[1-benzhydryl-2-(2-{[(2-bromophenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-chloro-2,4-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4-chloro-2,5-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-chloro-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(7-methoxy-2,1,3-benzoxadiazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)thien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[5-(2-methyl-1,3-thiazol-4-yl)thien-2-yl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-[2-(1-benzhydryl-5-chloro-2-{2-[(thien-3-ylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-[3-(1-benzhydryl-5-chloro-2-{2-[(thien-3-ylsulfonyl)amino]ethyl}-1H-indol-3-yl)propyl]benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(6-morpholin-4-ylpyridin-3-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-(2-{1-benzhydryl-2-[2-(benzo[1,2,5]oxadiazole-4-sulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)benzoic acid;4-(3-{1-benzhydryl-2-[2-(benzo[1,2,5]oxadiazole-4-sulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-propyl)benzoic acid;4-(2-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-ethoxy)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-isopropoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-(2-isopropoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoic acid;4-(3-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl]-5-chloro-1H-indol-3-yl}-propyl)benzoic acid;4-(3-{1-benzhydryl-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-(2-hydroxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-(2-chloro-6-methyl-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-2-fluoro-benzoic acid;N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-1-(3,4-dichlorophenyl)methanesulfonamide;N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetrazol-5-yl)-phenoxy]-ethyl}-1H-indol-2-yl)-ethyl]-2-chlorobenzenesulfonamide;N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]butane-1-sulfonamide;N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2H-tetraazol-5-yl)phenoxy]ethyl}-1H-indol-2-yl)ethyl]-2,2,2-trifluoroethanesulfonamide;4-(2-{1-benzhydryl-5-chloro-2-[2-(2,4,6-trifluoro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-(3-trifluoromethoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-(2,4,6-trifluoro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-(4-methoxy-2-nitro-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid; and4-(3-{1-benzhydryl-5-chloro-2-[2-(3-trifluoromethoxy-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid; or a pharmaceutically acceptablesalt thereof.
 45. The method of claim 1, wherein the compound isselected from:4-{3-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(5-methyl-1-phenyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,3-dichlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(4′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(4′-fluoro-1,1′-biphenyl-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid; and4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3-chloro-4-fluorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid; or a pharmaceutically acceptable salt thereof. 46.The method of claim 1, wherein the compound is selected from:4-[2-(2-{2-[2-(4-acetyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)-ethoxy]-benzoic acid; 4-[2-(1-benzhydryl-5-chloro-2-{2-[2-(3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoic acid;4-[2-(2-{2-[2-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-ethanesulfonylamino]-ethyl}-1-benzhydryl-5-chloro-1H-indol-3-yl)-ethoxy]-benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(4-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(3-methylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-[2-(1-benzhydryl-2-{2-[2-(2-carbamoyl-pyrrolidin-1-yl)-ethanesulfonylamino]-ethyl}-5-chloro-1 H-indol-3-yl)-ethoxy ]-benzoic acid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-ethylpiperidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethyl}sulfonyl)amino]ethyl}-1H-indol-3-l)ethoxy]benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-oxa-5-azabicyclo[2.2.1]hept-5-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-isopropylpyrrolidin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-methyl-3-oxopiperazin-1-yl)ethyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxylbenzoicacid;4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-2yl]ethyl}sulfonyl)benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]propanoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-4-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-5-fluoro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-nitrophenyl)sulfonylamino}ethyl)-1H-indol-3-yl]ethoxy}benzoic acid;4-[2-(1-benzhydryl-5-chloro-2-{2-[(mesitylsulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-(2,4,6-trimethyl-benzenesulfonylamino)-ethyl]-1H-indol-3-yl}-propyl)-benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-fluoro-6-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-diethylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid; and or a pharmaceutically acceptable salt thereof.
 47. The methodof claim 1, wherein the compound is selected from:4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-dimethylbenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[3-(1-benzhydryl-5-chloro-2-{2-[(cyclopropylsulfonyl)amino]-ethyl}-1H-indol-3-yl)propyl]benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-phenylethyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-dichlorophenyl)sulfanyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoicacid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(2,4-difluorophenyl)thio]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;4-[2-(1-benzhydryl-5-chloro-2-{2-[({[(3,4-dichlorophenyl)sulfinyl]methyl}sulfonyl)amino]ethyl}-1H-indol-3-yl)ethoxy]benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-hydroxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;N-{2-[1-benzhydryl-5-chloro-3-(2-{4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}ethyl)-1H-indol-2-yl]ethyl}-1-(3,4-dichlorophenyl)methanesulfonamide;N-[2-(1-benzhydryl-5-chloro-3-{2-[4-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenoxy]ethyl}-1H-indol-2-yl)-ethyl]-2-methyl-benzenesulfonamide;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(1-methyl-1H-imidazol-2-yl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{3-[1-benzhydryl-2-(2-{[(2-chlorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoicacid;3-[4-({2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)phenyl]-2,2-dimethylpropanoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-methoxybenzoicacid; and4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-isopropoxybenzoicacid; or a pharmaceutically acceptable salt thereof.
 48. The method ofclaim 1, wherein the compound is selected from:4-{3-[5-chloro-1-(diphenylmethyl)-2-(2-{[(2-nitrobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(methylsulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(methylsulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-[3-(1-benzhydryl-2-{2-[(1,1′-biphenyl-3-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3-yl)propyl]benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[5-chloro-2-(2-{[(2,6-difluorophenyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-(3-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-{3-[1-benzhydryl-2-(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]propyl}benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-{3-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]propyl}benzoicacid;4-(3-{1-benzhydryl-5-chloro-2-[2-({[2-(2-chloro-1-methylethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}propyl)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(methylsulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(methylsulfonyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-[2-(1-benzhydryl-2-{2-[(1,1′-biphenyl-3-ylsulfonyl)amino]ethyl}-5-chloro-1H-indol-3yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[3-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2,6-difluorophenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chloro-6-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[4-(trifluoromethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-(2-{5-chloro-1-(diphenylmethyl)-2-[2-({[2-(trifluoromethoxy)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-methoxyphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-{2-[1-benzhydryl-2-(2-{[(2-tert-butylphenyl)sulfonyl]amino}ethyl)-5-chloro-1H-indol-3-yl]ethoxy}benzoicacid; and4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(methylthio)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;4-{2-[1-benzhydryl-5-chloro-2-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}benzoicacid;4-[2-(1-benzhydryl-2-{2-[(benzylsulfonyl)amino]ethyl}-5-nitro-1H-indol-3-yl)ethoxy]benzoicacid;4-(2-{1-benzhydryl-5-chloro-2-[2-({[2-(2-chloro-1-methylethyl)phenyl]sulfonyl}amino)ethyl]-1H-indol-3-yl}ethoxy)benzoic acid;3-(2-(1-benzhydryl-5-chloro-2-(2-(phenylmethylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid;3-(2-(1-benzhydryl-5-chloro-2-(2-((3,4-dichlorophenyl)methylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid;2-(2-(1-benzhydryl-5-chloro-2-(2-(phenylmethylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid; and2-(2-(1-benzhydryl-5-chloro-2-(2-((3,4-dichlorophenyl)methylsulfonamido)ethyl)-1H-indol-3-yl)ethoxy)benzoic acid; or a pharmaceutically acceptable salt thereof.